Substituted polyamines as inhibitors of bacterial efflux pumps

a technology of bacterial efflux pump and substituted polyamine, which is applied in the direction of antibiotics, drug compositions, applications, etc., can solve problems such as therapeutic failures, and achieve the effects of increasing susceptibility to drugs, decreasing the translocation of these agents, and increasing the affinity of nitrogenous substrates

Inactive Publication Date: 2011-09-08
PARATEK PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0013]In another embodiment, the invention relates to a method of enhancing the antimicrobial activity of a drug comprising contacting a microbe that is resistant to one or more drugs with a drug to which the microbe is resistant and an inhibitor compound of the invention that is an inhibitor of an efflux pump to thereby enhance the antimicrobial activity of a drug.
[0017]Inhibitors of bacterial efflux pumps may generally be made by the chemical modification of polyamines, aminoglycosides, and other amine containing scaffolds. Suitable chemical modifications may increase the affinity of the nitrogenous substrate for bacterial antibiotic efflux proteins, thereby decreasing the translocation of these agents across the bacterial membrane. These efflux blocking compounds may be administered alone to inhibit the efflux of microbial waste products or environmental toxins or with a drug (e.g., an antibiotic or non-antibiotic agent to increase susceptibility to the drug.

Problems solved by technology

Drug efflux proteins in microbes can mediate resistance causing therapeutic failures.

Method used

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  • Substituted polyamines as inhibitors of bacterial efflux pumps
  • Substituted polyamines as inhibitors of bacterial efflux pumps
  • Substituted polyamines as inhibitors of bacterial efflux pumps

Examples

Experimental program
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example 1

Preparation of Substituted Polyamines

[0151]In general, polyamines may be derivatized using by, e.g., reductive amination with aryl aldehydes. Suitable polyamines include spermidine, spermine, norspermidine, spergaulin, 1,3,5-triamimocyclohexane, agrbactin, acyria pigments, and other products possessing 2 or more chemically modifiable amines. The polyamine substitution pattern may reside on one, two or three or more ring systems interconnected and in any pattern in a 3-D array.

[0152]For example, paromomycin derivatives (FIG. 2 and Table 2) are aminoglycosides possessing five primary amino functional groups (FIG. 1 and Table 1) and were produced by 5-N-benzylation using unsubstituted or substituted benzaldehydes under reduction by sodium borohydride. Many of these polysubstituted paromomycins are substrates of the efflux system of Haemophilus influenzae (Table 3) and act in synergy with tetracycline, doxycycline, and gentamicin to increase antibiotic susceptibility in H. influenzae (T...

example 2

Susceptibility of Haemophilus influenzae to Various Paromomycin Derivatives

[0155]AcrAB deleted strains of H. influenzae were constructed (see, e.g., Provence, D. L. and R. Curtiss III. (1994) In P. Gerhardt, R. G. E. Murray, W. A. Wood, and N. R. Krieg. (ed.), “Methods for General and Molecular Bacteriology,” American Society for Microbiology, Washington. pp. 317-347). Deletion of acrAB was confirmed by the absence of intact target DNA in a PCR assay.

[0156]MICs of selected antimicrobial agents were determined by a standard broth microdilution procedure with cation adjusted Mueller Hinton broth (Becton Dickinson, Cockeysville, Md.) and an inoculum of 5×105 CFU / ml according to NCCLS performance and interpretive guidelines (NCCLS. 1997. Methods for dilution antimicrobial susceptibility. Tests for bacteria that grow aerobically, Fourth Edition; Approved Standard. NCCLS document M7 A4 (ISBN 1 56238 309 4). NCCLS, 940 West Valley Road, Suite 1400, Wayne, Pa. 19087). Antimicrobial agents t...

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Abstract

Disclosed are methods of treating bacterial infections including those caused by multidrug resistant bacteria using polyamine efflux pump inhibiting compounds, including for example N-benzylated polyazaalkanes, N-benzylated polyaminoalkanes, or mixed N-benzylated poly(aza / amino)alkanes, optionally in combination with other drugs such as antibiotics, as well as pharmaceutical compositions thereof.

Description

RELATED APPLICATIONS[0001]This application is a continuation application of U.S. application Ser. No. 10 / 754,041, filed on Jan. 7, 2004, issuing; which claims priority to U.S. Provisional Patent Application No. 60 / 438,754, “Substituted Polyamines as Inhibitors of Bacterial Efflux Pumps” filed on Jan. 8, 2003, U.S. Provisional Patent Application No. 60 / 438,653, “Substituted Polyamines as Inhibitors of Bacterial Efflux Pumps” filed on Jan. 8, 2003, and to U.S. Provisional Patent Application No. 60 / 438,725, “Substituted Polyamines as Inhibitors of Bacterial Efflux Pumps” filed on Jan. 7, 2003. The entire contents of each of these patent applications are hereby incorporated herein by reference in their entirety.BACKGROUND[0002]Microbes have developed several different mechanisms of resistance to antibiotics and chemotherapeutic agents. These mechanisms of resistance can be specific, e.g., for a molecule or a family of molecules (e.g., antibiotics), or can be non-specific and be involved...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/706A61K31/7036A61P31/00A61P31/16C12N1/00C07G11/00A61K31/00A61K31/132A61K31/133A61K31/70
CPCA61K31/00A61K31/132A61K31/133A61K31/70A61K31/7036A61K2300/00A61P31/00A61P31/16Y02A50/30
Inventor NELSON, MARK L.ALEKSHUN, MICHAEL N.
Owner PARATEK PHARM INC
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