Novel use

Abstract

The present invention relates to compounds, and pharmaceutical compositions containing these compounds, for use in the treatment or prevention of infections caused by Klebsiella bacteria, in particular, urinary tract infections (UTIs).

Description

[0001] NOVEL USE

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to the treatment or prevention of infections caused by Klebsiella bacteria. In particular, the invention relates to the treatment or prevention of urinary tract infections (UTIs) caused by Klebsiella pneumoniae.

[0004] BACKGROUND TO THE INVENTION

[0005] Klebsiella is a genus of gram-negative bacteria within the Enterobacteriaceae family. Examples of bacteria falling in the Klebsiella genus are Klebsiella pneumoniae (Klebsiella pneumoniae), Klebsiella oxytoca, Klebsiella aerogenes, and Klebsiella variicola.

[0006] Klebsiella pneumoniae are gram-negative bacteria that are known to cause a variety of different infections. These infections include but are not limited to pneumonia, intra-abdominal infections, surgical wound infections, bloodstream infections, and urinary tract infections (UTIs).

[0007] UTIs are one of the most common bacterial infections, with between 50% and 60% of adult women having at least one UTI within their lifetime and thus UTIs affect around 150 million people each year (M. Medina, E. Castillo-Pino, TherAdv Uroi., 2019, Vol. 11, 3-7; W. E. Stamm, S. Ragnar Norrby, J Infect Dis, 2001, Vol. 183, S1-S4). Along with patient burden there is also a huge economic burden caused by UTIs, for example in the US each year the societal costs are approximated to be around $3.5 billion (A. L. Flores-Mireles et al., Nat Rev Microbiol., 2015, Vol. 13, 269-284).

[0008] Common methods of treatment or prevention of UTIs include the administration of antibiotics. However, resistance to these antibiotics has been growing among uropathogens, especially gram-negative bacteria. There is therefore a need for novel ways of treating or preventing UTIs.

[0009] The international patent application published as W02020 / 012336 discloses compounds that are FimH antagonists, that have been shown to be useful in the treatment and / or prevention of infections caused by Escherichia coli(E coll). The mechanism of action of antagonizing the E coii type 1 pilus adhesin molecule FimH provides an alternative treatment for E. coii caused infections other than by antibiotics.

[0010] Although the majority of UTIs are caused by E. coii, Klebsiella pneumoniaeave, one of the next largest cause of UTIs. Approximately 6% of uncomplicated UTIs and 8% of complicated UTIs are caused by Klebsiella pneumoniae (M. Medina, E. Castillo-Pino, Ther Adv Uroi., 2019, Vol. 11, 3-7).

[0011] There therefore exists a need in the art for a new method of treatment and / or prevention of infections caused by Klebsiella bacteria. SUMMARY OF THE INVENTION

[0012] The present invention provides Compound I: or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of an infection caused by Klebsiella bacteria.

[0013] According to a second aspect of the invention, there is provided a pharmaceutical composition for use in the treatment or prevention of an infection caused by Klebsiella bacteria, wherein the composition comprises (a) Compound or a pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable excipient.

[0014] According to a third aspect of the invention, there is provided a method for the treatment or prevention of an infection caused by Klebsiella bacteria in a human in need thereof comprising administering to said human a therapeutically effective amount of Compound I pharmaceutically acceptable salt thereof.

[0015] According to a fourth aspect of the invention, there is provided a method for the treatment or prevention of an infection caused by Klebsiella bacteria in a human in need thereof comprising administering to said human a therapeutically effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises: (a) Compound (I) (I) or a pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable excipient.

[0016] According to a fifth aspect of the invention, there is provided the use of Compound I pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of an infection caused by Klebsiella bacteria.

[0017] Compound I for use according to this invention may be advantageous in a number of respects.

[0018] Compound I has been described in W02020 / 012336 as an antagonist of FimH which can be used to treat infections caused by E coll It has now been found that Compound I can be used to treat infections caused by Klebsiella bacteria as well as to prevent infections caused by Klebsiella bacteria. Specifically, Compound I can be used to treat or prevent infections caused by Klebsiella pneumoniae strains. Specifically, Compound I can be used to treat or prevent UTIs caused by Klebsiella pneumoniae strains.

[0019] Certain antibiotics are the current treatment or preventative choice for infections caused by Klebsiella bacteria, particularly infections caused by Klebsiella pneumoniae. It is known in the art that antibiotics may suffer from antibiotic resistance. However, it is believed that Compound I in contrast to antibiotics, may be effective against both antibiotic resistant strains and nonantibiotic resistant strains of Klebsiella bacteria, particularly Klebsiella pneumoniae. Additionally, Compound I may be used to treat and prevent UTIs caused by Klebsiella pneumoniae in patients with a contraindication, allergy, or intolerance to antibiotics.

[0020] DESCRIPTION OF FIGURES

[0021] FIG. 1 shows the study design for acute UTI post-super-infection treatment experiments showing timeline of events.

[0022] FIG. 2 shows efficacy at 48 hours post infection for Compound I following ql2h subcutaneous administration or SMZ-TMP, ciprofloxacin, or nitrofurantoin following ql2h oral administration in an acute cystitis post-superinfection high inoculum (109per infection CFU) treatment model in mice caused by Klebsiella pneumoniae strain TOP52; Symbols indicate = - 2-Logio drop from pretreat and vehicle. Raw CFU counts were logic transformed and graphed with bars representing the mean and standard deviation of the data.

[0023] FIG. 3 shows efficacy at 48 hours post infection for Compound I following ql2h subcutaneous administration or SMZ-TMP following ql2h oral administration in an acute cystitis post- superinfection high inoculum (109per infection CFU) treatment model in mice caused by Klebsiella pneumoniae strain JMI-57; Symbols indicate §- 2-Logio drop from pre-treat and vehicle. Raw CFU counts were logic transformed and graphed with bars representing the mean and standard deviation of the data.

[0024] FIG. 4 shows efficacy at 48 hours post infection for Compound I following ql2h subcutaneous administration or SMZ-TMP following ql2h oral administration in an acute cystitis post- superinfection high inoculum (109per infection CFU) treatment model in mice caused by Klebsiella pneumoniae strain JMI-64; Symbols indicate = - 2-Logio drop from pre-treat and vehicle. Raw CFU counts were logic transformed and graphed with bars representing the mean and standard deviation of the data.

[0025] FIG. 5 shows efficacy at 48 hours post infection of Compound I following ql2h subcutaneous administration or SMZ-TMP following ql2h oral administration in an acute cystitis post- superinfection high inoculum (109per infection CFU) treatment model in mice caused by Klebsiella pneumoniae strain JMI-75; Symbols indicate §- 2-Logio drop from pre-treat and vehicle. Raw CFU counts were logic transformed and graphed with bars representing the mean and standard deviation of the data.

[0026] FIG. 6 shows efficacy at 48 hours post infection of Compound I following ql2h subcutaneous administration or SMZ-TMP following q!2h oral administration in an acute cystitis post- superinfection high inoculum (109per infection CFU) treatment model in mice caused by UPEC strain UTI89; Symbols indicate §- 2-Logio drop from pre-treat and vehicle. Raw CFU counts were logic transformed and graphed with bars representing the mean and standard deviation of the data.

[0027] FIG. 7 shows efficacy at 48 hours post infection of Compound I following ql2h subcutaneous administration or SMZ-TMP following ql2h oral administration in an acute cystitis post- superinfection high inoculum (109per infection CFU) treatment model in mice caused by Klebsiella pneumoniae strain JMI-82; Symbols indicate = - 2-Logio drop from vehicle. Raw CFU counts were logic transformed and graphed with bars representing the mean and standard deviation of the data.

[0028] FIG. 8 shows efficacy at 48 hours post infection of Compound I following ql2h subcutaneous administration or SMZ-TMP following ql2h oral administration in an acute cystitis post- superinfection high inoculum (109per infection CFU) treatment model in mice caused by Klebsiella pneumoniae strain JMI-92; Symbols indicate §- 2-LoglO drop from vehicle. Raw CFU counts were logic transformed and graphed with bars representing the mean and standard deviation of the data. In pilot studies, JMI-92 demonstrated low positive predictive value (PPV) (0.35) with regard to high urine titers at 24h accurately predicting high bladder burdens at 48h, despite the ability of this strain to yield high bladder burdens.

[0029] FIG. 9 shows the study design for in vivo dose ranging experiments showing the timeline of events.

[0030] FIG. 10 shows efficacy of Compound I or SMZ-TMP and ciprofloxacin (Cipro) in a prophylaxis model of acute cystitis in mice caused by uropathogenic Klebsiella pneumoniae reference isolate TOP52. Compound I and antimicrobials delivered once, 30 minutes prior to the initial infection.

[0031] FIG. 11 shows efficacy of Compound I or SMZ-TMP and ciprofloxacin (Cipro) in a prophylaxis model of acute cystitis in mice caused by uropathogenic Klebsiella pneumoniae isolate JMI-57. Compound I and antimicrobials delivered once, 30 minutes prior to the initial infection.

[0032] FIG. 12 shows efficacy of Compound I or SMZ-TMP and ciprofloxacin (Cipro) in a prophylaxis model of acute cystitis in mice caused by uropathogenic Klebsiella pneumoniae isolate JMI-64. Compound I and antimicrobials delivered once, 30 minutes prior to the initial infection.

[0033] FIG. 13 shows efficacy of Compound I or SMZ-TMP and ciprofloxacin (Cipro) in a prophylaxis model of acute cystitis in mice caused by uropathogenic Klebsiella pneumoniae isolate JMI-82. Compound I and antimicrobials delivered once, 30 minutes prior to the initial infection. DETAILED DESCRIPTION OF THE INVENTION

[0034] DEFINITIONS

[0035] The term "pharmaceutically acceptable" refers to those compounds (including salts), materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0036] As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-l,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5- dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hexyl resorcinate, hippurate, hydrabamine (N,N'- di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene-l,5-disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p- aminobenzenesulfonate, p-aminosalicyclate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, p- toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate. Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2- (hydroxymethyl)-l,3-propanediol (TRIS, tromethamine), arginine, benethamine (N- benzylphenethylamine), benzathine (N,N'-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p chlorobenzyl-2-pyrrolildine-l'- ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, t-butylamine, and zinc.

[0037] The term "treatment", "treat", or "treating" refers to ameliorating or stabilising the specified symptomatic condition, reducing or eliminating the symptoms of the condition, and slowing or eliminating the progression of the symptomatic condition, in a patient or subject.

[0038] The term "prevention", "prevent", "preventing", or "prophylaxis" refers to avoidance of the symptomatic condition in a subject who is not suffering from the specified condition or to the avoidance or delay of reoccurrence of the symptoms in a previously afflicted patient or subject who is currently asymptomatic.

[0039] The term "therapeutically effective amount" refers to the quantity of a compound or a pharmaceutically acceptable salt thereof, which will elicit the desired biological response in a human body. It may vary depending on the compound, the disease and its severity and the age and weight of the subject to be treated.

[0040] The term "antibiotic resistant" refers to a form of the bacterium which resists the effects of, or has reduced or no susceptibility to, one or more antibiotics.

[0041] The term "subject" refers to a human.

[0042] STATEMENT OF THE INVENTION

[0043] The present invention provides Compound I: or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of an infection caused by Klebsiella bacteria.

[0044] In an embodiment of the present invention, there is provided Compound I or a pharmaceutically acceptable salt thereof for use in the treatment of an infection caused by Klebsiella bacteria. In another embodiment of the present invention, there is provided Compound I or a pharmaceutically acceptable salt thereof for use in the prevention of an infection caused by Klebsiella bacteria. Klebsiella is a genus of gram-negative bacteria within the Enterobacteriaceae family. Examples of bacteria falling in the Klebsiella genus are Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella aerogenes, and Klebsiella variicola.

[0045] In particular, the present invention provides Compound I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of an infection caused by Klebsiella pneumoniae.

[0046] Compound I may also be known as (2R,3S,4S,5S,6R)-2-((R)-(3',5'-difluoro-3-methyl-[l,l'- biphenyl]-4-yl)(hydroxy)methyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. Compound I is referred to interchangeably herein as either Compound I or the compound of the invention. The parent molecule, Compound I, can be synthesized according to the international patent application published as W02020 / 012336, wherein Compound I is disclosed in example 9 of the publication. W02020 / 012336 is hereby incorporated by reference in its entirety. Specifically, example 9 of W02020 / 012336, detailing the method of making Compound I, is incorporated by reference.

[0047] It is to be understood that the references herein to Compound I or a pharmaceutically acceptable salt thereof includes Compound I as a parent compound, or as a pharmaceutically acceptable salt. Thus, in one embodiment, the invention is directed to Compound I. In another embodiment, the invention is directed to a pharmaceutically acceptable salt of Compound I. In another embodiment, the invention is directed to Compound I or a pharmaceutically acceptable salt thereof.

[0048] The present invention is directed to an infection caused by Klebsiella bacteria. In an embodiment the infection caused by Klebsiella bacteria is a urinary tract infection. In a further embodiment the urinary tract infection is caused by Klebsiella pneumoniae.

[0049] Compound I or a pharmaceutically acceptable salt thereof is provided for use in the treatment or prevention of a condition resulting from a Klebsiella infection. In an embodiment the condition is a urinary tract infection (UTI).

[0050] Compound I or a pharmaceutically acceptable salt thereof is provided for use in the treatment or prevention of a Klebsiella infection. In an embodiment the Klebsiella infection is a Klebsiella pneumoniae infection.

[0051] In an embodiment the infection is a urinary tract infection caused by Klebsiella bacteria. In an embodiment the infection is a urinary tract infection caused by Klebsiella pneumoniae.

[0052] P urinary tract infection (UTI) may be classified as either an uncomplicated UTI or as a complicated UTI. As used herein "uncomplicated UTI" or "uUTI" or "uncomplicated urinary tract infection" are all terms used interchangeably. As used herein, "complicated UTI" or "cUTI" or "complicated urinary tract infection" are all terms used interchangeably. uUTIs and cUTIs are terms that form part of the state of art. For example, they may be defined according to the "Guidelines on Urological Infections", (European Urological Society), https: / / uroweb.org / guidelines / urological-infections dated May 2024. For example, an uUTI may be defined as an acute, sporadic, or recurrent lower (uncomplicated cystitis) and / or upper (uncomplicated pyelonephritis) UTI, limited to non-pregnant women with no known relevant anatomical and functional abnormalities within the urinary tract or comorbidities. For example, a clITI may be defined as a UTI that is not uncomplicated. In a narrower sense cUTI may be defined as a UTI in a patient with an increased chance of a complicated course: i.e. all men, pregnant women, patients with relevant anatomical or functional abnormalities of the urinary tract, indwelling urinary catheters, renal diseases, and / or with other concomitant immunocompromising diseases for example, diabetes. A catheter-associated UTI may be classified as a complicated UTI and may be defined as a UTI occurring in a person whose urinary tract is currently catheterised or has had a catheter in place within the past 48 hours.

[0053] In an embodiment, the infection is cystitis. In accordance with the present invention, "cystitis" refers to an infection of the bladder.

[0054] In an embodiment of the invention the UTI is an uncomplicated UTI or a complicated UTI. In an embodiment the UTI is complicated. In an embodiment the human with a complicated urinary tract infection is male. In an embodiment the human with a complicated urinary tract infection is female. In an embodiment, the UTI is a catheter-associated UTI. In an embodiment the UTI is complicated and is a catheter-associated UTI. In an embodiment the UTI is uncomplicated. In an embodiment the human with an uncomplicated urinary tract infection is female. In a further embodiment the human with an uncomplicated urinary tract infection is either an adult female or adolescent female. In a further embodiment the human with an uncomplicated urinary tract infection is either an adult female or an adolescent female, wherein the human is >12 years old. In an embodiment the UTI is cystitis. In a further embodiment the UTI is complicated and is cystitis. In a further embodiment the UTI is complicated, is cystitis, and the human with the complicated urinary tract infection is male. In a further embodiment the UTI is uncomplicated and is cystitis. In a further embodiment the UTI is uncomplicated and is cystitis and the human with the uUTI is female.

[0055] In embodiments of the invention where the infection is an uUTI, the infection may be an acute uUTI, a recurrent uUTI, or a recurrent and acute uUTI.

[0056] Recurrent and acute are terms that form part of the state of the art. For example, recurrent UTIs may be defined according to the "Guidelines on Urological Infections", (European Urological Society), https: / / uroweb.org / guidelines / urological-infections. For example, as stated in the Guidelines dated May 2024, a recurrent UTI may be defined as recurrences of uncomplicated and / or complicated UTIs, with a frequency of at least three UTIs / year or two UTIs in the last six months. For example, an acute UTI may be defined as a discrete infectious episode.

[0057] Thus, a human may have both a recurrent UTI and an acute UTI, if for example, they have had at least three acute UTIs in the last year and / or at least two acute UTIs in the last 6 months inclusive of a current acute infection. Thus, in one embodiment the UTI is acute. In one embodiment the UTI is recurrent and acute. In one embodiment the UTI is recurrent. According to a further embodiment the human has an acute UTI and has had at least three acute UTIs in the last year and / or at least two acute UTIs in the last 6 months.

[0058] In an embodiment, there is provided Compound I for use in the treatment or prevention of an infection caused by Klebsiella bacteria, wherein the infection is a UTI, in particular where the infection is an uncomplicated UTI.

[0059] In an embodiment, there is provided Compound I for use in the treatment or prevention of an infection caused by Klebsiella bacteria, wherein the infection is an uncomplicated UTI, in particular a recurrent UTI.

[0060] In an embodiment, there is provided Compound I for use in the treatment or prevention of an infection caused by Klebsiella bacteria, wherein the infection is a recurrent uncomplicated UTI.

[0061] In an embodiment, there is provided Compound I for use in the treatment or prevention of an infection caused by Klebsiella bacteria, wherein the infection is an uncomplicated UTI, in particular a recurrent UTI, wherein a subject to be treated has had at least three acute UTIs in the last year and / or at least two acute UTIs in the last 6 months.In a further embodiment the UTI is chronic.

[0062] The UTIs in the above embodiments may be in a human with any of or a combination of the following: a contraindication, an allergy, or an intolerance to Standard of Care (SoC) antibiotics. In one embodiment the human has a contraindication to SoC antibiotics. In one embodiment the human has an allergy to SoC antibiotics. In one embodiment the human has an intolerance to SoC antibiotics.

[0063] Compound I or a pharmaceutically acceptable salt thereof is for use in the treatment or prevention of an infection caused by Klebsiella bacteria.

[0064] As used herein, the phrase "infection caused by" means: (1) that the infection is suspected to be caused by the specified bacteria, for example due to clinical signs and symptoms, patient history, or local epidemiology, or (2) that the infection is proven or determined to be caused by the specified bacteria using any standard method.

[0065] In one embodiment of the invention, prior to the administration of Compound I or a pharmaceutically acceptable salt thereof, the infection is determined to be caused by Klebsiella bacteria. In a further embodiment of the invention, prior to the administration of Compound I or a pharmaceutically acceptable salt thereof, the infection is determined to be caused by Klebsiella pneumoniae.

[0066] The determination may be done by any suitable means. For example, a sample such as a urine, plasma, or tissue sample may be obtained from a human suspected of having an infection caused by Klebsiella bacteria, the sample is then tested for the presence of Klebsiella bacteria, using any suitable means. If this sample reveals the presence of Klebsiella bacteria, Compound I or a pharmaceutically acceptable salt thereof is administered to the human suspected of having an infection caused by Klebsiella bacteria. The determination may be done by using one or more standard techniques. The determination may be done using one or more of the following techniques: matrix-assisted laser desorption / ionization-time of flight mass spectrometry (MALDI- TOF MS), analytical profile index (API) strip, MicroScan system, and Vitek. In an embodiment, testing may be through one or more of the following techniques: matrix-assisted laser desorption / ionization-time of flight mass spectrometry (MALDI-TOF MS), analytical profile index (API) strip, MicroScan system, and Vitek.

[0067] In some embodiments of the invention, Compound I or a pharmaceutically acceptable salt thereof is administered to a patient without first performing a diagnostic test to determine the cause of the infection. The present invention may reduce the need for diagnostic methods for determination of the bacterial cause of UTIs as Compound I is effective against infections caused by either E Coll or Klebsiella pneumoniae. As E Coii and Klebsiella pneumoniae cause. 81% of ullTIs and 73% of clITIs (M. Medina, E. Castillo-Pino, Ther Adv Uroi., 2019, Vol. 11, 3-7), Compound I may be administered to patients with UTIs without the need for a diagnostic test to determine the bacterial cause.

[0068] According to another embodiment of the invention, the human has previously had one or more infections caused by Klebsiella bacteria. In a further embodiment the human has previously had one or more infections caused by Klebsiella bacteria and the current infection is determined to be caused by Klebsiella bacteria. In a further embodiment, the human has previously had one or more infections caused by Klebsiella pneumoniae. In a further embodiment the human has previously had one or more infections caused by Klebsiella pneumoniae and the current infection is determined to be caused by Klebsiella pneumoniae. In an alternative embodiment, the human has previously had one or more infections caused by E Coii or Klebsiella bacteria and the current infection is determined to be caused by Klebsiella bacteria. Provided herein is Compound (I) for use in the treatment or prevention of a condition caused by a Klebsiella infection, in a subject in need thereof, wherein the subject has previously suffered from a condition or infection caused by E Coll or Klebsiella. In an embodiment, the condition or infection is a urinary tract infection.

[0069] In an embodiment, there is provided Compound I for use in the treatment or prevention of a recurrent UTI caused by Escherichia coii (E coii), wherein the subject to be treated has had a prior UTI caused by Klebsiella bacteria, in particular Klebsiella pneumoniae.

[0070] In an embodiment, there is provided Compound I for use in the treatment or prevention of a recurrent UTI caused by Klebsiella bacteria, wherein the subject to be treated has had a prior UTI caused by Klebsiella bacteria (in particular Klebsiella pneumoniae) or Escherichia coii (E. coii).

[0071] Klebsiella is a genus of gram-negative bacteria within the Enterobacteriaceae family. Klebsiella bacteria has a variety of antibiotic resistant mechanisms and thus can often be resistant to antibiotics. In the present invention, the Klebsiella bacteria may be antibiotic resistant, or it may become antibiotic resistant. In an embodiment of the invention the Klebsiella bacteria is antibiotic resistant. In another embodiment the Klebsiella bacteria is resistant to one or more antibiotics. In a further embodiment of the invention the Klebsiella bacteria is Klebsiella pneumoniae which is antibiotic resistant. In another embodiment the Klebsiella bacteria is Klebsiella pneumoniae which is resistant to one or more antibiotics.

[0072] In an embodiment, the Klebsiella bacteria is Klebsiella pneumoniae.

[0073] In a further embodiment the antibiotics that the Klebsiella bacteria may be resistant to or may become resistant to belong to any of the classes of penicillin, b-lactam combination agent, cephem, fluoroquinolone, nitrofuran, and folate pathway antagonist. In a further embodiment the antibiotics that the Klebsiella bacteria may be resistant to or may become resistant to are any one selected from the group consisting of ampicillin, amoxicillin / clavulanic acid (also known as AUGMENTIN), cefazolin, ceftriaxone, ciprofloxacin, levofloxacin, nitrofurantoin, trimethoprim, sulfamethoxazole, cefadroxil. In another embodiment the Klebsiella bacteria is not antibiotic resistant.

[0074] In a further embodiment the antibiotics that the Klebsiella pneumoniae may be resistant to or may become resistant to belong to any of the classes of penicillin, b-lactam combination agent, cephem, fluoroquinolone, nitrofuran, and folate pathway antagonist. In a further embodiment the antibiotics that Klebsiella pneumoniae may be resistant to or may become resistant to are any one selected from the group consisting of ampicillin, amoxicillin / clavulanic acid (also known as AUGMENTIN), cefazolin, ceftriaxone, ciprofloxacin, levofloxacin, nitrofurantoin, trimethoprim, sulfamethoxazole, cefadroxil. In another embodiment the Klebsiella pneumoniae is not antibiotic resistant.

[0075] As used herein, the phrase "is antibiotic resistant" covers an embodiment where the specified bacteria is antibiotic resistant at the time of initial infection and an embodiment where the specified bacteria has become antibiotic resistant after the time of initial infection. The phrase also covers the embodiment where the specified bacteria is resistant to one or more antibiotics at either timepoint.

[0076] Compound I can be administered in any suitable way and in any suitable form. In an embodiment of the invention, Compound I is administered in the form of a pharmaceutical composition, wherein the pharmaceutical composition comprises Compound I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In an embodiment of the invention, Compound I or the pharmaceutical composition is administered to the human orally.

[0077] According to a second aspect of the invention, there is provided a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for use in the treatment or prevention of an infection caused by Klebsiella bacteria.

[0078] Pharmaceutical compositions acceptable and adaptable for use in methods and / or uses of the present invention are prepared using conventional methods and may be adapted for administration by any appropriate route, for example orally.

[0079] In an embodiment, there is provided a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for use in the treatment of an infection caused by Klebsiella bacteria. In another embodiment, there is provided a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for use in the prevention of an infection caused by Klebsiella bacteria. In particular, there is provided a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for use in the treatment or prevention of an infection caused by Klebsiella pneumoniae.

[0080] In this aspect, there is provided a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Thus, in one embodiment this aspect is directed to a pharmaceutical composition comprising Compound I and a pharmaceutically acceptable excipient. In another embodiment, this aspect is directed to a pharmaceutical composition comprising a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient.

[0081] In an embodiment the infection is a urinary tract infection caused by Klebsiella bacteria. In an embodiment the infection is a urinary tract infection caused by Klebsiella pneumoniae.

[0082] The pharmaceutical composition is provided for use in the treatment or prevention of a condition resulting from a Klebsiella infection. In an embodiment the condition is a urinary tract infection (UTI).

[0083] In an embodiment of the invention the UTI is an uncomplicated UTI or a complicated UTI. In an embodiment the UTI is complicated. In an embodiment the human with a complicated urinary tract infection is male. In an embodiment the human with a complicated urinary tract infection is female. In an embodiment, the UTI is a catheter-associated UTI. In an embodiment the UTI is complicated and is a catheter-associated UTI. In an embodiment the UTI is uncomplicated. In an embodiment the human with an uncomplicated urinary tract infection is female. In a further embodiment the human with an uncomplicated urinary tract infection is either an adult female or adolescent female. In a further embodiment the human with an uncomplicated urinary tract infection is either an adult female or an adolescent female, wherein the human is >12 years old. In an embodiment the UTI is cystitis. In a further embodiment the UTI is complicated and is cystitis. In a further embodiment the UTI is complicated, is cystitis, and the human with the complicated urinary tract infection is male. In a further embodiment the UTI is uncomplicated and is cystitis. In a further embodiment the UTI is uncomplicated and is cystitis and the human with the ullTI is female.

[0084] In embodiments of the invention where the infection is an ullTI, the infection may be an acute ullTI, a recurrent ullTI, or a recurrent and acute ullTI.

[0085] Thus, in one embodiment the UTI is acute. In one embodiment the UTI is recurrent and acute. In one embodiment the UTI is recurrent. According to a further embodiment the human has an acute UTI and has had at least three acute UTIs in the last year and / or at least two acute UTIs in the last 6 months.

[0086] In an embodiment, there is provided a pharmaceutical composition for use in the treatment or prevention of an infection caused by Klebsiella bacteria, wherein the composition comprises (a) Compound I or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient, wherein the infection is a UTI, in particular where the infection is an uncomplicated UTI.

[0087] In an embodiment, there is provided Compound I for use in the treatment or prevention of an infection caused by Klebsiella bacteria, wherein the infection is an uncomplicated UTI, in particular a recurrent UTI.

[0088] In an embodiment, there is provided a pharmaceutical composition for use in the treatment or prevention of an infection caused by Klebsiella bacteria, wherein the composition comprises (a) Compound I or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient, wherein the infection is a recurrent uncomplicated UTI.

[0089] In an embodiment, there is provided a pharmaceutical composition for use in the treatment or prevention of an infection caused by Klebsiella bacteria, wherein the composition comprises (a) Compound I or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient, wherein the infection is an uncomplicated UTI, in particular a recurrent UTI, wherein a subject to be treated has had at least three acute UTIs in the last year and / or at least two acute UTIs in the last 6 months.

[0090] In a further embodiment the UTI is chronic.

[0091] In one embodiment the human has a contraindication to SoC antibiotics. In one embodiment the human has an allergy to SoC antibiotics. In one embodiment the human has an intolerance to SoC antibiotics.

[0092] In one embodiment of the invention, prior to the administration of the pharmaceutical composition, the infection is determined to be caused by Klebsiella bacteria. In a further embodiment of the invention, prior to the administration of the pharmaceutical composition, the infection is determined to be caused by Klebsiella pneumoniae.

[0093] In some embodiments of the invention, the pharmaceutical composition is administered to a patient without first performing a diagnostic test to determine the cause of the infection.

[0094] According to another embodiment of the invention, the human has previously had one or more infections caused by Klebsiella bacteria. In a further embodiment the human has previously had one or more infections caused by Klebsiella bacteria and the current infection is determined to be caused by Klebsiella bacteria. In a further embodiment, the human has previously had one or more infections caused by Klebsiella pneumoniae. In a further embodiment, the human has previously had one or more infections caused by Klebsiella pneumoniae and the current infection is determined to be caused by Klebsiella pneumoniae. In an alternative embodiment, the human has previously had one or more infections caused by E. Coiiov Klebsiella bacteria and the current infection is determined to be caused by Klebsiella bacteria. Provided herein is the pharmaceutical composition for use in the treatment or prevention of a condition caused by a Klebsiella infection, in a patient or subject in need thereof, wherein the patient or subject has previously suffered from a condition caused by E. Coll or Klebsiella. In an embodiment, the condition is a urinary tract infection.

[0095] In an embodiment of the invention the Klebsiella bacteria is antibiotic resistant. In another embodiment the Klebsiella bacteria is resistant to one or more antibiotics. In a further embodiment of the invention the Klebsiella bacteria is Klebsiella pneumoniae which is antibiotic resistant. In another embodiment the Klebsiella bacteria is Klebsiella pneumoniae which is resistant to one or more antibiotics.

[0096] In a further embodiment the antibiotics that the Klebsiella bacteria may be resistant to or may become resistant to belong to any of the classes of penicillin, b-lactam combination agent, cephem, fluoroquinolone, nitrofuran, and folate pathway antagonist. In a further embodiment the antibiotics that the Klebsiella bacteria may be resistant to or may become resistant to are any one selected from the group consisting of ampicillin, amoxicillin / clavulanic acid (also known as AUGMENTIN), cefazolin, ceftriaxone, ciprofloxacin, levofloxacin, nitrofurantoin, trimethoprim, sulfamethoxazole, cefadroxil. In another embodiment the Klebsiella bacteria is not antibiotic resistant.

[0097] In a further embodiment the antibiotics that the Klebsiella pneumoniae may be resistant to or may become resistant to belong to any of the classes of penicillin, b-lactam combination agent, cephem, fluoroquinolone, nitrofuran, and folate pathway antagonist. In a further embodiment the antibiotics that Klebsiella pneumoniae may be resistant to or may become resistant to are any one selected from the group consisting of ampicillin, amoxicillin / clavulanic acid (also known as AUGMENTIN), cefazolin, ceftriaxone, ciprofloxacin, levofloxacin, nitrofurantoin, trimethoprim, sulfamethoxazole, cefadroxil. In another embodiment the Klebsiella pneumoniae is not antibiotic resistant.

[0098] In an embodiment of the invention, the pharmaceutical composition is administered to the human orally.

[0099] According to a third aspect of the invention, there is provided a method for the treatment or prevention of an infection caused by Klebsiella bacteria in a human in need thereof comprising administering to said human a therapeutically effective amount of Compound I pharmaceutically acceptable salt thereof.

[0100] In an embodiment of the present invention, there is provided a method of treatment of an infection caused by Klebsiella bacteria in a human in need thereof comprising administering to said human a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof. In another embodiment of the present invention, there is provided a method of prevention of an infection caused by Klebsiella bacteria in a human in need thereof comprising administering to said human a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof.

[0101] In particular, the present invention provides a method for the treatment or prevention of an infection caused by Klebsiella pneumoniae '^ a human in need thereof comprising administering to said human, a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof.

[0102] In one embodiment, the invention is directed to Compound I. In another embodiment, the invention is directed to a pharmaceutically acceptable salt of Compound I. In another embodiment, the invention is directed to Compound I or a pharmaceutically acceptable salt thereof.

[0103] The present invention is directed to an infection caused by Klebsiella bacteria. In an embodiment, the present invention is directed to an infection caused by Klebsiella pneumoniae. In an embodiment the infection caused by Klebsiella bacteria is a urinary tract infection. In a further embodiment the urinary tract infection is caused by Klebsiella pneumoniae.

[0104] In one embodiment, there is provided a method for the treatment or prevention of a condition resulting from a Klebsiella infection. In an embodiment the condition is a urinary tract infection (UTI).

[0105] In one embodiment, there is provided a method for the treatment or prevention of a Klebsiella infection. In an embodiment the Klebsiella infection is a Klebsiella pneumoniae'\v &X\<yc\.

[0106] In an embodiment the infection is a urinary tract infection caused by Klebsiella bacteria. In an embodiment the infection is a urinary tract infection caused by Klebsiella pneumoniae.

[0107] In an embodiment of the invention the UTI is an uncomplicated UTI or a complicated UTI. In an embodiment the UTI is complicated. In an embodiment the human with a complicated urinary tract infection is male. In an embodiment the human with a complicated urinary tract infection is female. In an embodiment, the UTI is a catheter-associated UTI. In an embodiment the UTI is complicated and is a catheter-associated UTI. In an embodiment the UTI is uncomplicated. In an embodiment the human with an uncomplicated urinary tract infection is female. In a further embodiment the human with an uncomplicated urinary tract infection is either an adult female or adolescent female. In a further embodiment the human with an uncomplicated urinary tract infect is either an adult female or an adolescent female, wherein the human is >12 years old. In an embodiment the UTI is cystitis. In a further embodiment the UTI is complicated and is cystitis. In a further embodiment the UTI is complicated, is cystitis, and the human with the complicated urinary tract infection is male. In a further embodiment the UTI is uncomplicated and is cystitis. In a further embodiment the UTI is uncomplicated and is cystitis and the human with the uUTI is female.

[0108] In embodiments of the invention where the infection is an uUTI, the infection may be an acute uUTI, a recurrent uUTI, or a recurrent and acute uUTI.

[0109] In one embodiment the UTI is acute. In one embodiment the UTI is recurrent and acute. In one embodiment the UTI is recurrent. According to a further embodiment the human has an acute UTI and has had at least three acute UTIs in the last year and / or at least two acute UTIs in the last 6 months.

[0110] In an embodiment, there is provided a method for the treatment or prevention of an infection caused by Klebsiella bacteria in a subject in need thereof, comprising administering to subject a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof, wherein the infection is a UTI, in particular where the infection is an uncomplicated UTI.

[0111] In an embodiment, there is provided a method for the treatment or prevention of an infection caused by Klebsiella bacteria in a subject in need thereof, comprising administering to subject a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof, wherein the infection is an uncomplicated UTI, in particular a recurrent UTI.

[0112] In an embodiment, there is provided a method for the treatment or prevention of an infection caused by Klebsiella bacteria in a subject in need thereof, comprising administering to subject a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof, wherein the infection is a recurrent uncomplicated UTI.

[0113] In an embodiment, there is provided a method for the treatment or prevention of an infection caused by Klebsiella bacteria in a subject in need thereof, comprising administering to subject a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof, wherein the infection is an uncomplicated UTI, in particular a recurrent UTI, wherein a subject to be treated has had at least three acute UTIs in the last year and / or at least two acute UTIs in the last 6 months.

[0114] In a further embodiment the UTI is chronic. The UTIs in the above embodiments may be in a human with any of or a combination of the following: a contraindication, an allergy, or an intolerance to Standard of Care (SoC) antibiotics. In one embodiment the human has a contraindication to SoC antibiotics. In one embodiment the human has an allergy to SoC antibiotics. In one embodiment the human has an intolerance to SoC antibiotics.

[0115] In one embodiment of the invention, prior to the administration of Compound I or a pharmaceutically acceptable salt thereof, the infection is determined to be caused by Klebsiella bacteria. In a further embodiment of the invention, prior to the administration of Compound I or a pharmaceutically acceptable salt thereof, the infection is determined to be caused by Klebsiella pneumoniae.

[0116] In some embodiments of the invention, Compound I or a pharmaceutically acceptable salt thereof is administered to a patient without first performing a diagnostic test to determine the cause of the infection.

[0117] According to another embodiment of the invention, the human has previously had one or more infections caused by Klebsiella bacteria. In a further embodiment the human has previously had one or more infections caused by Klebsiella bacteria and the current infection is determined to be caused by Klebsiella bacteria. In a further embodiment, the human has previously had one or more infections caused by Klebsiella pneumoniae. In a further embodiment the human has previously had one or more infections caused by Klebsiella pneumoniae and the current infection is determined to be caused by Klebsiella pneumoniae. In an alternative embodiment, the human has previously had one or more infections caused by E. Coii or Klebsiella bacteria and the current infection is determined to be caused by Klebsiella bacteria. In an embodiment, there is provided a method for the treatment or prevention of a condition caused by a Klebsiella infection, comprising administration of a therapeutically effective amount of Compound (I) to a subject in need thereof, wherein the subject has previously suffered from a condition or infection caused by E. Coii or Klebsiella bacteria. In an embodiment, the condition or infection is a urinary tract infection.

[0118] In an embodiment, there is provided a method for the treatment or prevention of a recurrent UTI caused by Escherichia coii (E. coii), comprising administering to subject a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof, wherein the subject to be treated has had a prior UTI caused by Klebsiella bacteria, in particular Klebsiella pneumoniae.

[0119] In an embodiment, there is provided a method for the treatment or prevention of a recurrent UTI caused by Klebsiella, comprising administering to subject a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof, wherein the subject to be treated has had a prior UTI caused by Klebsiella bacteria (in particular Klebsiella pneumoniae) or Escherichia coii (E. coii). In an embodiment of the invention the Klebsiella bacteria is antibiotic resistant. In another embodiment the Klebsiella bacteria is resistant to one or more antibiotics. In a further embodiment of the invention the Klebsiella bacteria is Klebsiella pneumoniae which is antibiotic resistant. In another embodiment the Klebsiella bacteria is Klebsiella pneumoniae which is resistant to one or more antibiotics.

[0120] In a further embodiment the antibiotics that the Klebsiella bacteria may be resistant to or may become resistant to belong to any of the classes of penicillin, b-lactam combination agent, cephem, fluoroquinolone, nitrofuran, and folate pathway antagonist. In a further embodiment the antibiotics that the Klebsiella bacteria may be resistant to or may become resistant to are any one selected from the group consisting of ampicillin, amoxicillin / clavulanic acid (also known as AUGMENTIN), cefazolin, ceftriaxone, ciprofloxacin, levofloxacin, nitrofurantoin, trimethoprim, sulfamethoxazole, cefadroxil. In another embodiment the Klebsiella bacteria is not antibiotic resistant.

[0121] In a further embodiment the antibiotics that the Klebsiella pneumoniae may be resistant to or may become resistant to belong to any of the classes of penicillin, b-lactam combination agent, cephem, fluoroquinolone, nitrofuran, and folate pathway antagonist. In a further embodiment the antibiotics that Klebsiella pneumoniae may be resistant to or may become resistant to are any one selected from the group consisting of ampicillin, amoxicillin / clavulanic acid (also known as AUGMENTIN), cefazolin, ceftriaxone, ciprofloxacin, levofloxacin, nitrofurantoin, trimethoprim, sulfamethoxazole, cefadroxil. In another embodiment the Klebsiella pneumoniae is not antibiotic resistant.

[0122] In an embodiment of the invention, Compound I is administered in the form of a pharmaceutical composition, wherein the pharmaceutical composition comprises Compound I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In an embodiment of the invention, Compound I or the pharmaceutical composition is administered to the human orally.

[0123] According to a fourth aspect of the invention, there is provided a method for the treatment or prevention of an infection caused by Klebsiella bacteria in a human in need thereof comprising administering to said human a therapeutically effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises: (a) Compound (I)

[0124] (I) or a pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable excipient.

[0125] In one embodiment, there is provided a method of treatment of an infection caused by Klebsiella bacteria in a human in need thereof comprising administering to said human a therapeutically effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises: (a) Compound (I) or a pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable excipient. In one embodiment, there is provided a method of prevention of an infection caused by Klebsiella bacteria in a human in need thereof comprising administering to said human a therapeutically effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises: (a) Compound (I) or a pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable excipient.

[0126] In particular, there is provided a method of treatment or prevention of an infection caused by Klebsiella pneumoniae in a human in need thereof comprising administering to said human a therapeutically effective amount of a pharmaceutical composition comprising the Compound I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0127] In an embodiment the infection is a urinary tract infection caused by Klebsiella bacteria. In an embodiment the infection is a urinary tract infection caused by Klebsiella pneumoniae.

[0128] In an embodiment of the invention the UTI is an uncomplicated UTI or a complicated UTI. In an embodiment the UTI is complicated. In an embodiment the human with a complicated urinary tract infection is male. In an embodiment the human with a complicated urinary tract infection is female. In an embodiment, the UTI is a catheter-associated UTI. In an embodiment the UTI is complicated and is a catheter-associated UTI. In an embodiment the UTI is uncomplicated. In an embodiment the human with an uncomplicated urinary tract infection is female. In a further embodiment the human with an uncomplicated urinary tract infection is either an adult female or adolescent female. In a further embodiment the human with an uncomplicated urinary tract infect is either an adult female or an adolescent female, wherein the human is >12 years old. In an embodiment the UTI is cystitis. In a further embodiment the UTI is complicated and is cystitis. In a further embodiment the UTI is complicated, is cystitis, and the human with the complicated urinary tract infection is male. In a further embodiment the UTI is uncomplicated and is cystitis. In a further embodiment the UTI is uncomplicated and is cystitis and the human with the ullTI is female.

[0129] The embodiments of the invention where the infection is an ullTI, the infection may be an acute ullTI, a recurrent ullTI, or a recurrent and acute ullTI.

[0130] Thus, in one embodiment the UTI is acute. In one embodiment the UTI is recurrent and acute. In one embodiment the UTI is recurrent. According to a further embodiment the human has an acute UTI and has had at least three acute UTIs in the last year and / or at least two acute UTIs in the last 6 months.

[0131] In a further embodiment the UTI is chronic.

[0132] In one embodiment the human has a contraindication to SoC antibiotics. In one embodiment the human has an allergy to SoC antibiotics. In one embodiment the human has an intolerance to SoC antibiotics.

[0133] In one embodiment of the invention, prior to the administration of the pharmaceutical composition, the infection is determined to be caused by Klebsiella bacteria. In a further embodiment of the invention, prior to the administration of the pharmaceutical composition, the infection is determined to be caused by Klebsiella pneumoniae.

[0134] In some embodiments of the invention, the pharmaceutical composition is administered to a patient without first performing a diagnostic test to determine the cause of the infection.

[0135] According to another embodiment of the invention, the human has previously had one or more infections caused by Klebsiella bacteria. In a further embodiment the human has previously had one or more infections caused by Klebsiella bacteria and the current infection is determined to be caused by Klebsiella bacteria. In a further embodiment, the human has previously had one or more infections caused by Klebsiella pneumoniae. In a further embodiment the human has previously had one or more infections caused by Klebsiella pneumoniae and the current infection is determined to be caused by Klebsiella pneumoniae. In an alternative embodiment, the human has previously had one or more infections caused by E. Coiiov Klebsiella bacteria and the current infection is determined to be caused by Klebsiella bacteria. Therefore, in an embodiment, there is provided a method for the treatment or prevention of a condition caused by a Klebsiella infection, comprising administration of a therapeutically effective amount of the pharmaceutical composition to a patient or subject in need thereof, wherein the patient or subject has previously suffered from a condition caused by E. Coliov Klebsiella bacteria. In an embodiment, the condition is a urinary tract infection.

[0136] In an embodiment of the invention the Klebsiella bacteria is antibiotic resistant. In another embodiment the Klebsiella bacteria is resistant to one or more antibiotics. In a further embodiment of the invention the Klebsiella bacteria is Klebsiella pneumoniae which is antibiotic resistant. In another embodiment the Klebsiella bacteria is Klebsiella pneumoniae which is resistant to one or more antibiotics. In a further embodiment the antibiotics that the Klebsiella bacteria may be resistant to or may become resistant to belong to any of the classes of penicillin, b-lactam combination agent, cephem, fluoroquinolone, nitrofuran, and folate pathway antagonist. In a further embodiment the antibiotics that the Klebsiella bacteria may be resistant to or may become resistant to are any one selected from the group consisting of ampicillin, amoxicillin / clavulanic acid (also known as AUGMENTIN), cefazolin, ceftriaxone, ciprofloxacin, levofloxacin, nitrofurantoin, trimethoprim, sulfamethoxazole, cefadroxil. In another embodiment the Klebsiella bacteria is not antibiotic resistant.

[0137] In a further embodiment the antibiotics that the Klebsiella pneumoniae may be resistant to or may become resistant to belong to any of the classes of penicillin, b-lactam combination agent, cephem, fluoroquinolone, nitrofuran, and folate pathway antagonist. In a further embodiment the antibiotics that Klebsiella pneumoniae may be resistant to or may become resistant to are any one selected from the group consisting of ampicillin, amoxicillin / clavulanic acid (also known as AUGMENTIN), cefazolin, ceftriaxone, ciprofloxacin, levofloxacin, nitrofurantoin, trimethoprim, sulfamethoxazole, cefadroxil. In another embodiment the Klebsiella pneumoniae is not antibiotic resistant.

[0138] In an embodiment of the invention, the pharmaceutical composition is administered to the human orally.

[0139] According to a fifth aspect of the invention, there is provided the use of Compound I pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment or prevention of an infection caused by

[0140] Klebsiella bacteria.

[0141] In an embodiment of the present invention, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of an infection caused by Klebsiella bacteria. In another embodiment of the present invention, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the prevention of an infection caused by Klebsiella bacteria. In particular, the present invention provides the use of Compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment or prevention of an infection caused by Klebsiella pneumoniae.

[0142] In one embodiment, the invention is directed to Compound I. In another embodiment, the invention is directed to a pharmaceutically acceptable salt of Compound I. In another embodiment, the invention is directed to Compound I or a pharmaceutically acceptable salt thereof.

[0143] The present invention is directed to an infection caused by Klebsiella bacteria. In an embodiment the infection caused by Klebsiella bacteria is a urinary tract infection. In a further embodiment the urinary tract infection is caused by Klebsiella pneumoniae.

[0144] In an embodiment, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment or prevention of a condition caused by a Klebsiella infection. In an embodiment the condition is a urinary tract infection (UTI).

[0145] In an embodiment the Klebsiella infection is a Klebsiella pneumoniae infection.

[0146] In an embodiment the infection is a urinary tract infection caused by Klebsiella bacteria. In an embodiment the infection is a urinary tract infection caused by Klebsiella pneumoniae.

[0147] In an embodiment of the invention the UTI is an uncomplicated UTI or a complicated UTI. In an embodiment the UTI is complicated. In an embodiment the human with a complicated urinary tract infection is male. In an embodiment the human with a complicated urinary tract infection is female. In an embodiment, the UTI is a catheter-associated UTI. In an embodiment the UTI is complicated and is a catheter-associated UTI. In an embodiment the UTI is uncomplicated. In an embodiment the human with an uncomplicated urinary tract infection is female. In a further embodiment the human with an uncomplicated urinary tract infection is either an adult female or adolescent female. In a further embodiment the human with an uncomplicated urinary tract infect is either an adult female or an adolescent female, wherein the human is >12 years old. In an embodiment the UTI is cystitis. In a further embodiment the UTI is complicated and is cystitis. In a further embodiment the UTI is complicated, is cystitis, and the human with the complicated urinary tract infection is male. In a further embodiment the UTI is uncomplicated and is cystitis. In a further embodiment the UTI is uncomplicated and is cystitis and the human with the uUTI is female.

[0148] In embodiments of the invention where the infection is an uUTI, the infection may be an acute uUTI, a recurrent uUTI, or a recurrent and acute uUTI.

[0149] In one embodiment the UTI is acute. In one embodiment the UTI is recurrent and acute. In one embodiment the UTI is recurrent. According to a further embodiment the human has an acute UTI and has had at least three acute UTIs in the last year and / or at least two acute UTIs in the last 6 months.

[0150] In a further embodiment the UTI is chronic. In one embodiment the human has a contraindication to SoC antibiotics. In one embodiment the human has an allergy to SoC antibiotics. In one embodiment the human has an intolerance to SoC antibiotics.

[0151] In one embodiment of the invention, prior to the administration of Compound I or a pharmaceutically acceptable salt thereof, the infection is determined to be caused by Klebsiella bacteria. In a further embodiment of the invention, prior to the administration of Compound I or a pharmaceutically acceptable salt thereof, the infection is determined to be caused by Klebsiella pneumoniae.

[0152] In some embodiments of the invention, Compound I or a pharmaceutically acceptable salt thereof is administered to a patient without first performing a diagnostic test to determine the cause of the infection.

[0153] According to another embodiment of the invention, the human has previously had one or more infections caused by Klebsiella bacteria. In a further embodiment the human has previously had one or more infections caused by Klebsiella bacteria and the current infection is determined to be caused by Klebsiella bacteria. In a further embodiment, the human has previously had one or more infections caused by Klebsiella pneumoniae. In a further embodiment the human has previously had one or more infections caused by Klebsiella pneumoniae and the current infection is determined to be caused by Klebsiella pneumoniae. In an alternative embodiment, the human has previously had one or more infections caused by E. Coiiov Klebsiella bacteria and the current infection is determined to be caused by Klebsiella bacteria. In an embodiment, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a condition caused by a Klebsiella infection, comprising administration of a therapeutically effective amount of Compound (I) to a patient or subject in need thereof, wherein the patient or subject has previously suffered from a condition caused by E. Coliov Klebsiella bacteria. In an embodiment, the condition is a urinary tract infection.

[0154] In an embodiment of the invention the Klebsiella bacteria is antibiotic resistant. In another embodiment the Klebsiella bacteria is resistant to one or more antibiotics. In a further embodiment of the invention the Klebsiella bacteria is Klebsiella pneumoniae which is antibiotic resistant. In another embodiment the Klebsiella bacteria is Klebsiella pneumoniae which is resistant to one or more antibiotics.

[0155] In a further embodiment the antibiotics that the Klebsiella bacteria may be resistant to or may become resistant to belong to any of the classes of penicillin, b-lactam combination agent, cephem, fluoroquinolone, nitrofuran, and folate pathway antagonist. In a further embodiment the antibiotics that the Klebsiella bacteria may be resistant to or may become resistant to are any one selected from the group consisting of ampicillin, amoxicillin / clavulanic acid (also known as AUGMENTIN), cefazolin, ceftriaxone, ciprofloxacin, levofloxacin, nitrofurantoin, trimethoprim, sulfamethoxazole, cefadroxil. In another embodiment the Klebsiella bacteria is not antibiotic resistant.

[0156] In a further embodiment the antibiotics that the Klebsiella pneumoniae may be resistant to or may become resistant to belong to any of the classes of penicillin, b-lactam combination agent, cephem, fluoroquinolone, nitrofuran, and folate pathway antagonist. In a further embodiment the antibiotics that Klebsiella pneumoniae may be resistant to or may become resistant to are any one selected from the group consisting of ampicillin, amoxicillin / clavulanic acid (also known as AUGMENTIN), cefazolin, ceftriaxone, ciprofloxacin, levofloxacin, nitrofurantoin, trimethoprim, sulfamethoxazole, cefadroxil. In another embodiment the Klebsiella pneumoniae is not antibiotic resistant.

[0157] EXAMPLES

[0158] The Examples set forth below are illustrative of the present invention and are not intended to limit, in any way, the scope of the present invention. Those of skill in the art will recognise that in vivo assays for functional activity are subject to experimental variability. Accordingly, it is to be understood that the values given below are exemplary only.

[0159] 1. Treatment of infections caused by Klebsiella pneumoniae with Compound I

[0160] 1.1. Methods

[0161] 1.1.1. Animals

[0162] Specific pathogen free (SPF) 7-9-week-old female C3H / HeN mice (Envigo, Indianapolis, Indiana) were used throughout. At the start of each experiment, 10 mice were allocated to each treatment group.

[0163] 1.1.2. Organisms

[0164] The reference clinical Uropathogenic Escherichia coli (JJPEC) strain UTI89, isolated from a woman with uncomplicated cystitis (M. Mulvey et al., Infect Immun., 2001, 69(7), 4572- 4579), was used as a UPEC comparator. This strain is susceptible to sulfamethoxazoletrimethoprim, nitrofurantoin, and ciprofloxacin, the Standard of Care (SoC) antibiotics used in select studies. The antibiogram for UTI89 was generated by the Saint Louis University Hospital clinical microbiology laboratory using the Vitek 2 system. The reference clinical Klebsiella pneumoniae strain TOP52 was isolated from the urine of a woman with acute cystitis who proceeded to experience recurrent cystitis caused by the same Klebsiella pneumoniae strain (D. A. Rosen et al., PLoS Med, 4(12), 2007, e329; D. A. Rosen et al., Infect Immun., 2008, 76(7), 3337-3356). This strain is susceptible to sulfamethoxazole-trimethoprim and ciprofloxacin but is resistant to nitrofurantoin. The antibiogram forTOP52 was generated by the Saint Louis University Hospital clinical microbiology laboratory using the Vitek 2 system.

[0165] To study recent isolates with clinically relevant antibiotic resistances, additional clinical non-UPEC uropathogenic strains, including Klebsiella pneumoniae strains, were purchased from JMI Laboratories (North Liberty, Iowa). Strains that were identified as Klebsiella pneumoniae by JMI laboratories were randomised and screened for suitability in a 48-hour post super infection mouse model of acute cystitis. From this data, 5 Klebsiella pneumoniae strains were selected for use in collecting efficacy data, JMI-57, JMI-64, JMI-75, JMI-82, and JMI-92.

[0166] The demographics, strain characteristics, and antimicrobial susceptibility of the Klebsiella pneumoniae community-acquired UTI isolates used in these studies is shown in Table I below, where MIC is Minimum inhibitory concentration. Table I

[0167] To prepare the Klebsiella pneumoniae and UPEC strains for inoculation in mice, 20 mL of Luria-Bertani (LB) broth was inoculated from the freezer stock using a 10 pL sterile inoculating loop and grown statically in ambient air at 37°C overnight. The overnight culture was diluted into multiple aliquots (between 10 and 30 depending on the strain) of fresh media by adding 20 pL into 20 mL of LB broth per aliquot and subculturing statically at 37°C for a further 18 h. These cultures were centrifuged at room temperature for 10 min at 3,000 x g, resuspended in 5 mL phosphate-buffered saline, pH = 7.4 (PBS), and diluted to approximately 2-4 x 1010colony forming units (CFU) / mL by estimation using optical density (ODeoo ~ 35) to prepare the final suspension for the infection procedure.

[0168] 1.1.3. Infection

[0169] A graphical schematic for the infection model is shown in FIG. 1. Infections were carried out as follows:

[0170] Mice were inoculated with 109CFU / bladder at time 0 and again lh later, and infection was allowed to establish for 24h post first inoculation. At 24h, urine was collected for CFU / bladder screening, pre-treatment baseline controls were euthanised, and bladders collected for CFU / bladder determination, and all remaining mice were dosed with Compound I. Bladders were collected for CFU / bladder determination at 48h post first inoculation.

[0171] To determine the efficacy of Compound I against the 6 clinical Klebsiella pneumoniae strains and one clinical UPEC reference) strain (UTI89) in experimental urinary bladder infection studies in mice, an acute cystitis superinfection model initiated via two transurethral inoculations of bacteria into the urinary bladder was used (C.S. Hung et al., NatProtoc, 2009, 4(8), 1230-1243; D. J. Schwartz, PLoS Pathog, 2015, 11(1), el004599). Mice were anesthetized by inhalation of 3% isoflurane in 2.5 L / min of oxygen and 50 pL of the bacterial suspension was inoculated into the bladder of each mouse using a transurethral catheter to dispense approximately 1-2 x 109CFU / mouse. Mice were then returned to their cage and monitored until recovery. A second inoculum of approximately 1-2 x 109CFU / mouse was then administered as described, 1 hour after the initial infection.

[0172] It was found that a 24-hour post initial infection bacteriuria of >107CFU / mL urine had a high positive predictive value of subsequent high bladder bacterial burdens for all Klebsiella pneumoniae strains tested. In accordance with these preliminary data, for these studies, at 24 hours post initial infection urine was collected from all animals (across all groups) and CFU / mL of urine was determined. Urine CFU counts from all animals were enumerated after overnight growth for bladder bacterial burden assessment at 48 hours post initial infection. Animals with <107CFU / mL in urine were removed from the study at that time with no further assessments. All other animals (those with >107CFU / mL in urine at 24 hours post initial infection) were included in these 1 studies for bladder CFU counts. Statistical analysis and power calculations (for animal numbers) have taken these prior data and assumptions into consideration for data analysis.

[0173] 1.1.4. Administration of Compounds

[0174] The powder of Compound I was synthesized and analyzed to be 91.9% pure. However, the compound was used in all experiments at 100% total drug substance (i.e. no weighing correction factor was applied). The difference is considered negligible for interpretation of these Biology experiments. Ciprofloxacin was used as the non-formulated United States Pharmacopeia (USP) powder. Sulfa methoxazole-tri methoprim (Sulfamethoxazole and Trimethoprim Oral Suspension USP, 200 mg / 40 mg per 5 mL) was used as the commercial pharmaceutical grade suspension. Nitrofurantoin was used as the commercial pharmaceutical-grade powder in capsules in all other studies. The powder was removed from the capsules and corrected for excipients to prepare dosing formulations for mice.

[0175] Compound I was prepared in its parent form, as a 10.0 mg / mL solution in 10% 2-hydroxy- b-cyclodextrin in water (10% CD). It was administered by subcutaneous injection in a volume of 100 pL to achieve a dosage of 50.0 mg / kg. The dosages of the SoC comparators were determined using allometric scaling to convert the established human dosages (K. Gupta et al., din. Infect Dis., 2011, 52(5), el03-el20) to mouse equivalent dosing regimens using previously published methods (A. B. Nair, S. Jacob, J Basic din Pharm, 2016, 7(2), 27-31). Ciprofloxacin (Cipro) was prepared as a 10 mg / mL suspension in 10% CD; sulfamethoxazole-trimethoprim (SMZ-TMP) was prepared as a 40 mg / mL (34 mg / mL sulfamethoxazole and 6 mg / mL trimethoprim) suspension in 10% CD; and Nitrofurantoin (Nitro) was prepared as a 4 mg / mL suspension in 1.0% methylcellulose. Cipro, SMZ-TMP and Nitro were orally administered to mice in a volume of 100 pL to achieve dosages of 50 mg / kg, 167 / 33 mg / kg, and 20 mg / kg, respectively.

[0176] All compounds were freshly prepared immediately prior to each experiment. The same dosing preparations were used throughout the study and were maintained at room temperature between dosing intervals. An additional group of animals received 100 pL 10% CD vehicle and served as infected vehicle-treated controls (VTC). All groups of mice received their respective treatment at approximately 24 and 36 hours after the initial infection procedure (FIG. 1). Mice were assumed to weigh 20 g for calculation of dosing volume. Compound I was administered subcutaneously using a 27 G 0.5-inch needle. Ciprofloxacin, SMZ-TMP, and Nitro treatments were administered orally into the stomach using a 22-gauge, 1-inch gavage needle.

[0177] In these studies, Compound I was dosed twice daily at 24- and 36- (ql2h) hours post initial infection. Exp. 1 was a proof of principle study using the Klebsiella pneumoniae reference clinical strain TOP52. The rest of the experiments show the efficacy of Compound I against UPEC strain UTI89 (Exp. 5) and the 5 JMI Klebsiella pneumoniae isolates (JMI-57 (Exp. 2), JMI-64 (Exp. 3), JMI-75 (Exp. 4), JMI-82 (Exp. 6), and JMI-92 (Exp. 7)). Each of these 6 strains was treated twice daily with 50.0 mg / kg of Compound I resulting in a daily dose of 100.0 mg / kg, with the first dose given 24 hours post initial infection and the second dose given 36 hours post initial infection. Bladder samples were collected 48 hours post initial infection to assess bladder bacterial burdens.

[0178] 1.1.5. In iz / i / o samples

[0179] The in vivo studies described include a preliminary experiment with Klebsiella pneumoniae strain TOP52 followed by studies evaluating the efficacy of subcutaneous (SC) delivery of Compound I against the 5 remaining clinical Klebsiella pneumoniae strains and the UPEC strain UTI89. Bladders were excised aseptically, voided for urine, and homogenized in 200 pL PBS for 2 minutes (2 x 60 seconds with a 5-minute interval) using a FastPrep24 bead homogenizer with sterile 5 mm stainless steel beads. For enumeration of viable bacteria, PBS was added to samples to make a final volume of 1.0 mL, and these were serially diluted ten-fold in PBS and plated in 5 spots of 10 pL each onto Luria-Bertani (LB) agar plates using an electronic repeat multichannel pipettor. Following overnight incubation at 37°C, the lowest dilution row that contained between 15 and 150 colonies was counted by visual inspection for quantification of bacterial burden. The lower limit of quantification was 1.3 logic CFU / bladder.

[0180] 1.1.6. Data Handling and Analysis

[0181] Randomization: Mice were completely randomized into groups, without normalization by weight (i.e. a fully randomized design), using the Experimental Design Assistant tool from the National Centre for the Replacement Refinement & Reduction of Animals in Research (found at https: / / eda.nc3rs.org.uk / eda / landing).

[0182] Blinding: The primary endpoint was CFU / bladder. After spotting of the bladder homogenate dilution series onto LB plates, the culture plates were de-identified by placing a sticker over the ID and were randomized prior to incubation. After sufficient colony growth, the colonies were enumerated at the appropriate dilution (the lowest dilution with between 15 and 150 total colonies) and these counts were recorded directly on the culture plates. Once the quantitation was completed, the stickers were removed and the data was recorded for analysis.

[0183] Analysis: The outcome measure for in vivo comparison of treatments was the number of bacteria isolated from bladders (logic CFU / bladder) at the conclusion of the study. All results are presented as individual data points in the graph with group means and standard deviations.

[0184] 1.1.7. PD Analysis

[0185] The PD outcome measure for this study was the change in number of bacteria isolated from murine bladders (logic CFU / bladder) compared to the average CFU / bladder of pre-treatment baseline control mice at the end of the study. 1.1.8. Summan / of the Experiments

[0186] Exp. 1: Proof of principle study with TOP52, comparing Compound I and SMZ-TMP, Ciprofloxacin, and Nitro.

[0187] Exp. 2: Study with strain JMI-57

[0188] Exp. 3: Study with strain JMI-64

[0189] Exp. 4: Study with strain JMI-75

[0190] Exp. 5: Study with strain UTI89

[0191] Exp. 6: Study with strain JMI-82

[0192] Exp. 7: Study with strain JMI-92

[0193] 1.2 Results

[0194] 1.2.1 Studies with Klebsiella pneumoniae sxavn TOP52 (Exp. 1)

[0195] The initial efficacy study that was conducted with Klebsiella pneumoniae clinical reference strain TOP52 provided strong evidence that Compound I will be efficacious against acute cystitis caused by Klebsiella pneumoniae and that bladder bacterial burdens of Klebsiella pneumoniae can be reduced by subcutaneous administration of Compound I (FIG. 2). Exp. 1 using ql2h dosing (FIG. 2) shows that the 100 mg / kg daily dose of Compound I results in overall effects similar to Sulfa methoxazole-Tri methoprim (SMZ-TMP) and Ciprofloxacin (Cipro) treatment and resulted in >2-logio drops in CFU / bladder relative to both pre-treatment and vehicle treated controls.

[0196] 1.2.2 Efficacy studies with 5 additional Klebsiella pneumoni strain UTI89 (Exp.

[0197] 2, 3, 4, 5, 6, 7)

[0198] The studies described above resulted in the establishment of a standardized experimental design using ql2h dosing of Compound I at a 50.0 mg / kg per dose (100.0 mg / kg total daily dose). This standardized experimental design was then used to assess the efficacy of Compound I against the 5 JMI Klebsiella pneumoniae clinical strains and, to facilitate comparison to previous studies, the UPEC clinical reference strain UTI89. From these studies, it is found that Compound I is efficacious against all tested strains. Against infections caused by JMI-57, JMI-64, JMI-75, and UTI89 (FIG.

[0199] 3, FIG. 4, FIG. 5, and FIG. 6)), statistically significant >2-logio CFU reductions in bladder bacterial burdens relative to both pre-treatment and vehicle treated controls are achieved.

[0200] For JMI-82, Compound I does not achieve a 2-logio CFU drop relative to pre-treatment controls, the 50 mg / kg ql2h dose is 1.90-logio CFU lower than pre-treatment control (FIG. 7).

[0201] For JMI-92, 24 hours post infection (hpi) bacteriuria was unable to detect mice that were spontaneously clearing their infections; therefore, the bladder bacterial burdens of all infected mice were assessed, resulting in increased data spread and a lower mean pre-treatment control value. This resulted in a maximum logio CFU reduction relative to pre-treatment controls of 1.96 at the 50 mg / kg ql2h dose (FIG. 8). 1.3. Conclusion

[0202] These data show that subcutaneous administration of Compound I is effective against 6 clinical Klebsiella pneumoniae strains (TOP52, JMI-57, JMI-64, JMI-75, JMI-82, JMI-92) and the UPEC strain UTI89 in a mouse model of uncomplicated acute cystitis. Compound I demonstrates efficacy with all strains showing a >1.9-logio reduction in bladder bacterial burdens relative to pretreatment controls as shown in Figures 2 to 8. Compound I demonstrates efficacy of >2-logio reductions against 4 Klebsiella pneumoniae strains (TOP52, JMI-57, JMI-64, JMI-75) and UTI89. Compound I demonstrates efficacy of >1.9-logio reductions against JMI-82 and JMI-92.

[0203] 2. Prophylaxis of infections caused by Klebsiella pneumoniae Compound I

[0204] 2.1 Methods

[0205] 2.1.1 Animals

[0206] Specific pathogen free (SPF) 8-10-week-old female C3H / HeN mice (Envigo, Indianapolis, Indiana) were used throughout. At the start of each experiment, 10 mice were allocated to each treatment group, unless otherwise noted.

[0207] All procedures were performed in accordance with protocols approved by the Saint Louis University Institutional Animal Care and Use Committee and met or exceeded the standards of the American Association for the Accreditation of Laboratory Animal Care (AAALAC), the United States Department of Health and Human Services and all local and federal animal welfare laws.

[0208] 2.1.2 Organisms

[0209] The reference clinical Klebsiella pneumoniae strain TOP52 was isolated from the urine of a woman with acute cystitis who proceeded to experience recurrent cystitis caused by the same Klebsiella pneumoniae strain (D. A. Rosen et al., PLoS Med, 4(12), 2007, e329; D. A. Rosen et al., Infect Immun., 2008, 76(7), 3337-3356). This strain is susceptible to sulfamethoxazole-trimethoprim and ciprofloxacin but is resistant to nitrofurantoin. The antibiogram for TOP52 was generated by the Saint Louis University Hospital clinical microbiology laboratory using the Vitek 2 system.

[0210] To study recent isolates with clinically relevant antibiotic resistances, additional clinical uropathogenic Klebsiella pneumoniae strains were purchased from International Health Management Associates (IHMA), Inc (Schaumburg, IL) and JMI Laboratories (North Liberty, Iowa). The Klebsiella pneumoniae strains used in this study include JMI-57, JMI-64, and JMI-82. Previous experiments with these strains demonstrated their ability to establish robust bladder colonization in mouse models of acute cystitis following super infection with 2 inoculations of 109CFU per inoculation given 1 hour apart.

[0211] To prepare the Klebsiella pneumoniae strains for inoculation in mice, 20 mL of Luria-Bertani (LB) broth was inoculated from the freezer stock using a 10 pL sterile inoculating loop and grown statically in ambient air at 37°C overnight. The overnight culture was diluted into multiple aliquots (between 20 and 30 depending on the strain) of fresh media by adding 20 pL into 20 mL of LB broth per aliquot and subculturing statically at 37°C for a further 18 h. These cultures were centrifuged at room temperature for 10 min at 3,000 x g, resuspended in 10 mL phosphate- buffered saline, pH = 7.4 (PBS), and diluted to approximately 2-4 x 1010colony forming units (CFU) / mL by estimation using optical density (OD600 ~ 35) to prepare the final suspension for the infection procedure.

[0212] 2.1.3 Infection

[0213] A graphical schematic for the infection model is shown in FIG. 9. Briefly, mice were dosed with Compound I, or antibiotic comparator or vehicle, 30 minutes prior (time -0.5h) to initial bacterial inoculation with 109CFU / bladder (as described below) at time 0. The bacterial inoculation was repeated lh later, and infection was allowed to establish for 24h post first inoculation. Urine was collected just prior to the first inoculation (~25 minutes post-dosing) and again at 23.5h post inoculation (24h post-dosing) to measure concentration of Compound I, and bladders were collected for CFU / bladder determination at 24h post first inoculation.

[0214] To determine the efficacy of Compound I against the 4 clinical Klebsiella pneumoniae strains in experimental urinary bladder infection studies in mice, an acute cystitis superinfection model initiated via two transurethral inoculations of bacteria into the urinary bladder was used (C.S. Hung et al., NatProtoc, 2009, 4(8), 1230-1243; D. J. Schwartz, PLoS Pathog, 2015, 11(1), el004599). Mice were anesthetized by inhalation of 3% isoflurane in 2.5 L / min of oxygen and 50 pL of the bacterial suspension was inoculated into the bladder of each mouse using a transurethral catheter to dispense approximately 1-2 x 109CFU / mouse. Mice were then returned to their cage and monitored until recovery. A second inoculum of approximately 1-2 x 109CFU / mouse was then administered as described, 1 hour after the initial infection.

[0215] 2.1.4 Administration of Compounds

[0216] The powder of Compound I was synthesized and analysed and found to be 91.0% pure. However, the compound was used in all experiments at 100% total drug substance (i.e. no weighing correction factor was applied). This difference is considered negligible for interpretation of these Biology experiments. Ciprofloxacin (Cipro) was used as the non-formulated USP powder. Sulfa methoxazole-tri methoprim (SMZ-TMP) (Sulfamethoxazole and Trimethoprim Oral Suspension USP, 200 mg / 40 mg per 5 mL) was used as the commercial pharmaceutical grade suspension.

[0217] Compound I was prepared in its parent form, absent of salt or hydration, as 10.0 mg / mL solutions in 10% 2-hydroxy-p-cyclodextrin in water (10% CD). It was administered by subcutaneous injection in a volume of 100 pL to achieve a dosage of 50.0 mg / kg, respectively. The dosages of the antibiotic comparators were determined using allometric scaling to convert the established human dosages (K. Gupta et al., din. Infect Dis., 2011, 52(5), el03-el20) to mouse equivalent dosing regimens using previously published methods (A. B. Nair, S. Jacob, J Basic din Pharm, 2016, 7(2), 27-31). Ciprofloxacin (Cipro) was prepared as a 10 mg / mL suspension in 10% CD and sulfamethoxazole-trimethoprim (SMZ-TMP) was prepared as a 40 mg / mL (34 mg / mL sulfamethoxazole and 6 mg / mL trimethoprim) suspension in 10% CD. Cipro and SMZ-TMP were orally administered to mice in a volume of 100 pL to achieve dosages of 50 mg / kg and 167 / 33 mg / kg, respectively.

[0218] All compounds were freshly prepared immediately prior to each experiment. The same dosing preparations were used throughout the study and were maintained at room temperature between dosing intervals. An additional group of animals received 100 pL 10% CD vehicle and served as infected vehicle-treated controls (VTC). All groups of mice received their respective treatment 30 minutes prior to the initial infection procedure (FIG. 9). Mice were assumed to weigh 20 g for calculation of dosing volume. Compound I was administered subcutaneously using a 27 G 0.5-inch needle. Antibiotic treatments were administered orally into the stomach using a 22-gauge, 1-inch gavage needle.

[0219] In these studies, Compound I was dosed once at 30 minutes prior to the initial infection. Infections caused by each of the 4 Klebsiella pneumoniae strains were treated with 50.0 mg / kg of Compound I. Bladder samples were collected 24 hours post initial infection to assess bladder bacterial burdens.

[0220] 2.1.5 In / O samples

[0221] The in vivo studies described evaluate the efficacy of subcutaneous delivery of Compound I against the 4 clinical Klebsiella pneumoniae strains. In these prophylaxis experiments, the determination of bacterial numbers present in the urinary bladder at the time when treatment was initiated (i.e. infection baseline or pre-treatment samples) was not possible as the mice were treated prior to infection; therefore, the vehicle treated control groups were the primary comparator. Bladders were excised aseptically, voided for urine, and homogenized in 200 pL PBS for 2 minutes (2 x 60 seconds with a 5-minute interval) using a FastPrep24 bead homogenizer with sterile 5 mm stainless steel beads. For enumeration of viable bacteria, PBS was added to samples to make a final volume of 1.0 mL, and these were serially diluted ten-fold in PBS and plated in 5 spots of 10 pL each onto Luria-Bertani (LB) agar plates using an electronic repeat multichannel pipettor. Following overnight incubation at 37°C, the lowest dilution row that contained between 15 and 150 colonies was counted by visual inspection for quantification of bacterial burden. The lower limit of quantification was 1.3 logic CFU / bladder.

[0222] 2.1.6 Data Handling and Analysis

[0223] Randomization: Mice were completely randomized into groups, without normalization by weight (i.e. a fully randomized design), using the Experimental Design Assistant tool from the National Centre for the Replacement Refinement & Reduction of Animals in Research (found at https: / / eda.nc3rs.org.uk / eda / landing).

[0224] Blinding: The primary endpoint was CFU / bladder. After spotting of the bladder homogenate dilution series onto LB plates, the culture plates were de-identified by placing a sticker over the ID and then randomized prior to incubation. After sufficient colony growth, the colonies were enumerated at the appropriate dilution (the lowest dilution with between 15 and 150 colonies / 50 pL) and the counts were recorded directly on the culture plates. Once the quantitation was completed, the stickers were removed and the data was recorded for analysis. QC was performed on the data entry, ensuring that the counts were properly recorded, and the integrity of the data analysis was ensured.

[0225] Analysis: The outcome measure for in vivo comparison of treatments was the number of bacteria isolated from bladders (logic CFU / bladder) at the conclusion of the study. All results are presented as individual data points in the graph with group means and standard deviations.

[0226] 2.1.7 Pharmacodynamic (PD) Analysis

[0227] For PD studies for Klebsiella pneumoniae in the prophylaxis murine model of acute cystitis, the outcome measure was the number of bacteria isolated from bladders (logic CFU / bladder) at the conclusion of the study.

[0228] Against infections caused by TOP52 (FIG. 10), JMI-57 (FIG. 11), JMI-64 (FIG. 12), JMI-82 (FIG 13.), Compound I was able to prophylactically demonstrate a significant reduction of bacterial burden, within the bladder, relative to vehicle-treated mice.

[0229] 2.1.8 Summan / of the Experiments

[0230] Exp. 8: Prophylactic study with strain TOP52

[0231] Exp. 9: Prophylactic study with strain JMI-57

[0232] Exp. 10: Prophylactic study with strain JMI-64

[0233] Exp. 11: Prophylactic study with strain JMI-82

[0234] 2.2 Results In these studies, the administration of Compound I, 30 minutes prior to infection, demonstrated a significant reduction of bacterial burden, within the bladder, relative to vehicle-treated mice. Compound I was tested against 4 Klebsiella pneumoniae clinical isolates (TOP52, JMI-57, JMI-64, and JMI-82) and achieved >2-logio reductions against all strains tested (>3.0-logio reductions against all strains, except JMI-82) when compared with vehicle-treated mice. These data demonstrate efficacy of Compound I in preventing acute cystitis caused by diverse Klebsiella pneumoniae strains.

[0235] 2.3 Conclusion

[0236] Compound I was tested against 4 Klebsiella pneumoniae clinical isolates (TOP52, JMI-57, JMI-64, and JMI-82) and achieved >2-logio reductions against all strains tested (>3.0-logio reductions against all strains, except JMI-82) when compared with vehicle-treated mice as shown in Figures 10 to 13. Compound I shows efficacy in the prevention of acute cystitis caused by diverse Klebsiella pneumoniae strains. This also shows Compound I may be effective in the prevention of recurrent cystitis caused by diverse Klebsiella pneumoniae straps. It will be understood that the present invention has been described above purely by way of example, and modification of detail can be made within the scope of the invention. Each feature disclosed in the description, and where appropriate the claims and drawings may be provided independently or in any appropriate combination.

Claims

CLAIMS1. Compound Ipharmaceutically acceptable salt thereof, for use in the treatment or prevention of an infection caused by Klebsiella bacteria.Compound Ipharmaceutically acceptable salt thereof, for use in the treatment of an infection caused by Klebsiella bacteria.

3. Compound Ipharmaceutically acceptable salt thereof, for use in the prevention of an infection caused by Klebsiella bacteria.

4. A pharmaceutical composition for use in the treatment or prevention of an infection caused by Klebsiella bacteria, wherein the composition comprises (a) Compound (I)pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable excipient.The compound for use or the pharmaceutical composition for use according to any one of the preceding claims, wherein the infection is a urinary tract infection (UTI).The compound for use or the pharmaceutical composition for use according to Claim 5, wherein the urinary tract infection (UTI) is uncomplicated.The compound for use or the pharmaceutical composition for use according to Claim 5 or 6, wherein the urinary tract infection (UTI) is recurrent.The compound for use or the pharmaceutical composition for use according to Claim 7, wherein the infection is in a human who has had at least three acute UTIs in the last year and / or at least two acute UTIs in the last 6 months.

9. The compound for use or the pharmaceutical composition for use according to Claim 5, wherein the urinary tract infection (UTI) is complicated.

10. The compound for use or the pharmaceutical composition for use according to any one of Claims 5 to 9, wherein the urinary tract infection (UTI) is cystitis.

11. The compound for use or the pharmaceutical composition for use according to any one of Claims 5 to 6 and Claims 9 to 10, wherein the urinary tract infection (UTI) is acute.

12. The compound for use or the pharmaceutical composition for use according to any one of Claims 5 to 11, wherein the urinary tract infection (UTI) is chronic.

13. The compound for use or the pharmaceutical composition for use according to any one of the preceding claims, wherein the Klebsiella bacteria is selected from the group consisting of Klebsiella oxytoca, Klebsiella aerogenes, Klebsiella variicola, and Klebsiella pneumoniae.

14. The compound for use or the pharmaceutical composition for use according to any one of the preceding claims, wherein the Klebsiella bacteria is antibiotic resistant.

15. The compound for use or the pharmaceutical composition for use according to any one of the preceding claims, wherein the Klebsiella bacteria is Klebsiella pneumoniae.

16. The compound for use or the pharmaceutical composition for use according to any one of the preceding claims, wherein the compound or the pharmaceutical composition is adapted for oral administration.

17. The compound for use or the pharmaceutical composition for use according to Claim 16, wherein the compound or the pharmaceutical composition is in the form of a tablet or a capsule.

18. The compound for use or the pharmaceutical composition for use according to any one of the preceding claims, wherein prior to the administration of the compound or the pharmaceutical composition, the infection is determined to be caused by Klebsiella bacteria.

19. The compound for use or the pharmaceutical composition for use according to any one of the preceding claims, wherein the infection is in a human who has previously had one or more infections caused by Escherichia coii (E. coii) ov Klebsiella bacteria.

20. The compound for use or the pharmaceutical composition for use according to claim 18, wherein prior to administration of the compound or the pharmaceutical composition, the infection is determined to be caused by Klebsiella pneumoniae.

21. The compound for use or the pharmaceutical composition for use according to Claim 19, wherein the infection is in a human who has previously had one or more infections caused by Escherichia coll (E. coll) or Klebsiella pneumoniae.

22. P method of treatment or prevention of an infection caused by Klebsiella bacteria in a human in need thereof comprising administering to said human a therapeutically effective amount of Compound Ipharmaceutically acceptable salt thereof.

23. A method of treatment of an infection caused by Klebsiella bacteria in a human in need thereof comprising administering to said human a therapeutically effective amount of Compound Ipharmaceutically acceptable salt thereof.

24. A method of prevention of an infection caused by Klebsiella bacteria in a human in need thereof comprising administering to said human a therapeutically effective amount of Compound Ipharmaceutically acceptable salt thereof.

25. A method of treatment of an infection caused by Klebsiella bacteria in a human in need thereof comprising administering to said human a therapeutically effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises: (a) Compound (I)pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable excipient.

26. The method of treatment or prevention according to any one of claims 22 to 25, wherein the infection is a urinary tract infection (UTI).

27. The method of treatment or prevention according to Claim 26, wherein the urinary tract infection (UTI) is uncomplicated.

28. The method of treatment or prevention according to Claim 26 or Claim 27, wherein the urinary tract infection (UTI) is recurrent.

29. The method of treatment or prevention according to Claim 28, wherein the infection is in a human who has had at least three acute UTIs in the last year and / or at least two acute UTIs in the last 6 months.

30. The method of treatment or prevention according to Claim 26, wherein the urinary tract infection (UTI) is complicated.

31. The method of treatment or prevention according to any one of Claims 26 to 30, wherein the urinary tract infection (UTI) is cystitis.

32. The method of treatment or prevention according to any one of Claims 26 to 27 and 30 to 31, wherein the urinary tract infection (UTI) is acute.

33. The method of treatment or prevention according to any one of Claims 26 to 32, wherein the urinary tract infection (UTI) is chronic.

34. The method of treatment or prevention according to any one of Claims 22 to 33, wherein the Klebsiella bacteria is selected from the group consisting of Klebsiella oxytoca, Klebsiella aerogenes, Klebsiella variicola, and Klebsiella pneumoniae.

35. The method of treatment or prevention according to any one of Claims 22 to 34, wherein the Klebsiella bacteria is antibiotic resistant.

36. The method of treatment or prevention according to any one of Claims 22 to 35, wherein the Klebsiella bacteria is Klebsiella pneumoniae.

37. The method of treatment or prevention according to any one of Claims 22 to 36, wherein the compound or the pharmaceutical composition is adapted for oral administration.

38. The method of treatment or prevention according to Claim 37, wherein the compound or the pharmaceutical composition is in the form of a tablet or a capsule.

39. The method of treatment or prevention according to any one of Claims 22 to 38, wherein prior to the administration of the compound or the pharmaceutical composition, the infection is determined to be caused by Klebsiella bacteria.

40. The method of treatment or prevention according to any one of Claims 22 to 39, wherein the infection is in a human who has previously had one or more infections caused by Escherichia coii (E. coii) or Klebsiella bacteria.

41. The method of treatment or prevention according to Claim 39, wherein prior to administration of the compound or the pharmaceutical composition, the infection is determined to be caused by Klebsiella pneumoniae.

42. The method of treatment or prevention according to Claim 40, wherein the infection is in a human who has previously had one or more infections caused by Escherichia coii (E. coii) or Klebsiella pneumoniae.

43. Use of Compound Ipharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of an infection caused by Klebsiella bacteria.

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