Iridoid compound and application of metabolite of iridoids compound in preparing drug-resistance bacterium infection resisting drug

Abstract

The invention relates to an iridoid compound with the general formula I-III and application of the in-vivo metabolite of the iridoid compound in preparing a drug-resistance bacterium infection resisting drug. It is found through in-vivo and in-vitro MRBS resisting experiments that the iridoid compound and the metabolite of the iridoid compound have remarkable drug-resistance bacterium resisting activity and can be used for being developed into the drug-resistance bacterium resisting drug.

Description

technical field

[0001] The invention relates to a class of iridoid compounds and uses thereof, in particular to the use of the iridoid compounds in inhibiting methicillin-resistant Staphylococcus aureus. The present invention also relates to the main in vivo metabolites of the iridoid compounds used as drugs for anti-drug-resistant bacterial infections, pharmaceutical compositions containing them, their in vivo and in vitro anti-drug-resistant bacterial activities, and methods of use. Background technique

[0002] The emergence of bacterial resistance and the infection of drug-resistant bacteria often make empiric treatment difficult to be effective, which brings great challenges to clinical anti-infective treatment. The emergence of methicillin-resistant Staphylococcus aureus (MRSA) is an increasingly serious problem after the widespread use of antibiotics in clinic: common antibiotics are difficult to work, although vancomycin is the most effective antibiotic for MRSA infe...

Examples

experiment example 1

[0026] Experimental Example 1: Separation and structure identification of in vivo metabolites of syringpicroside A

[0027] Syringin A was ultrasonically dissolved in drinking water, administered orally to 20 male SD rats at a dose of 100 mg / kg, and the urine was collected for a total of 20 days. A total of 2.4 L of urine was collected and stored in a freezer. The collected urine was extracted four times with ethyl acetate and n-butanol respectively. The ethyl acetate layer extract and the n-butanol layer extract were concentrated respectively, and the endogenous substances were tracked in parallel with blank urine through various column chromatography methods, and the in vivo metabolites of syringpicroside A in urine were analyzed. Separation and purification, a total of 9 metabolites were isolated, the metabolic pathway is as follows.

[0028]

Embodiment 2

[0029] Embodiment 2: The determination of the minimum inhibitory concentration (MIC) of iridoids and metabolites to 4 kinds of bacteria

[0030] Tested strains: Staphylococcus aureus (MSSA)

[0031] Methicillin-resistant Staphylococcus aureus (MRSA)

[0032] Penicillin-resistant Streptococcus pneumoniae (PRSP)

[0033] Vancomycin-resistant enterococci (VRE) were clinically isolated from the Laboratory Department of the 463rd Hospital of the People's Liberation Army.

[0034] Drugs and reagents: vancomycin hydrochloride for injection (VH, Eli Lilly Japan K.K); normal saline (Shandong Yuwang Industrial Co., Ltd.). Beef extract; peptone; NaCl; NaOH (Tianjin Bodi Chemical Co., Ltd.); water (sterile water).

[0035] Medium: Mueller-Hinton (MH) Broth Medium (g / L):

[0036]

[0037] Accurately weigh various components, stir and mix well, then add NaOH to adjust the pH to 7.2-7.4. Sterilize under high pressure steam at 0.1MPa for 30min.

[0038] Test compounds: Syringopicrosi...

experiment example 3

[0046] Experimental example 3: Determination of in vivo anti-Staphylococcus aureus infection activity of syringpicroside A (compound 1)

[0047]Select 72 Kunming mice, randomly divide them into 9 groups, 8 in each group, and mark them as blank group (K), positive group (VH), syringpicroside A high-dose group (Sy-H), syringpicroside A Medium dose group (Sy-M), syringpicroside A low dose group (Sy-L) and clove leaf group (DXY). After intragastric administration, methicillin-resistant Staphylococcus aureus (10 9 CFU / ml) 2 times, 0.1ml / 10g for the first time, 0.15ml / 10g for the second time. The administration was continued, and the number of deaths in each group was observed after 7 days.

[0048] Grouping and dosing are as follows:

[0049] Blank group: normal saline

[0050] VH group (positive group): vancomycin hydrochloride (300mg / kg, clinical dose)

[0051] DXY group (clove leaf group): clove leaf (82.2mg / kg, calculated as tablet core)

[0052] Sy-L group (low dose grou...

technical field

[0001] The invention relates to a class of iridoid compounds and uses thereof, in particular to the use of the iridoid compounds in inhibiting methicillin-resistant Staphylococcus aureus. The present invention also relates to the main in vivo metabolites of the iridoid compounds used as drugs for anti-drug-resistant bacterial infections, pharmaceutical compositions containing them, their in vivo and in vitro anti-drug-resistant bacterial activities, and methods of use. Background technique

[0002] The emergence of bacterial resistance and the infection of drug-resistant bacteria often make empiric treatment difficult to be effective, which brings great challenges to clinical anti-infective treatment. The emergence of methicillin-resistant Staphylococcus aureus (MRSA) is an increasingly serious problem after the widespread use of antibiotics in clinic: common antibiotics are difficult to work, although vancomycin is the most effective antibiotic for MRSA infe...

Examples

experiment example 1

[0026] Experimental Example 1: Separation and structure identification of in vivo metabolites of syringpicroside A

[0027] Syringin A was ultrasonically dissolved in drinking water, administered orally to 20 male SD rats at a dose of 100 mg / kg, and the urine was collected for a total of 20 days. A total of 2.4 L of urine was collected and stored in a freezer. The collected urine was extracted four times with ethyl acetate and n-butanol respectively. The ethyl acetate layer extract and the n-butanol layer extract were concentrated respectively, and the endogenous substances were tracked in parallel with blank urine through various column chromatography methods, and the in vivo metabolites of syringpicroside A in urine were analyzed. Separation and purification, a total of 9 metabolites were isolated, the metabolic pathway is as follows.

[0028]

Embodiment 2

[0029] Embodiment 2: The determination of the minimum inhibitory concentration (MIC) of iridoids and metabolites to 4 kinds of bacteria

[0030] Tested strains: Staphylococcus aureus (MSSA)

[0031] Methicillin-resistant Staphylococcus aureus (MRSA)

[0032] Penicillin-resistant Streptococcus pneumoniae (PRSP)

[0033] Vancomycin-resistant enterococci (VRE) were clinically isolated from the Laboratory Department of the 463rd Hospital of the People's Liberation Army.

[0034] Drugs and reagents: vancomycin hydrochloride for injection (VH, Eli Lilly Japan K.K); normal saline (Shandong Yuwang Industrial Co., Ltd.). Beef extract; peptone; NaCl; NaOH (Tianjin Bodi Chemical Co., Ltd.); water (sterile water).

[0035] Medium: Mueller-Hinton (MH) Broth Medium (g / L):

[0036]

[0037] Accurately weigh various components, stir and mix well, then add NaOH to adjust the pH to 7.2-7.4. Sterilize under high pressure steam at 0.1MPa for 30min.

[0038] Test compounds: Syringopicrosi...

experiment example 3

[0046] Experimental example 3: Determination of in vivo anti-Staphylococcus aureus infection activity of syringpicroside A (compound 1)

[0047]Select 72 Kunming mice, randomly divide them into 9 groups, 8 in each group, and mark them as blank group (K), positive group (VH), syringpicroside A high-dose group (Sy-H), syringpicroside A Medium dose group (Sy-M), syringpicroside A low dose group (Sy-L) and clove leaf group (DXY). After intragastric administration, methicillin-resistant Staphylococcus aureus (10 9 CFU / ml) 2 times, 0.1ml / 10g for the first time, 0.15ml / 10g for the second time. The administration was continued, and the number of deaths in each group was observed after 7 days.

[0048] Grouping and dosing are as follows:

[0049] Blank group: normal saline

[0050] VH group (positive group): vancomycin hydrochloride (300mg / kg, clinical dose)

[0051] DXY group (clove leaf group): clove leaf (82.2mg / kg, calculated as tablet core)

[0052] Sy-L group (low dose grou...

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