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Redesign of the Carbapenem Scaffold

Award Information

Agency:
Department of Health and Human Services
Branch:
N/A
Award ID:
Program Year/Program:
2012 / STTR
Agency Tracking Number:
R41AI102507
Solicitation Year:
2012
Solicitation Topic Code:
NIAID
Solicitation Number:
PA11-097
Small Business Information
THERAVANCE, INC.
901 GATEWAY BLVD SOUTH SAN FRANCISCO, CA 94080-7024
View profile »
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
 
Phase 1
Fiscal Year: 2012
Title: Redesign of the Carbapenem Scaffold
Agency: HHS
Contract: 1R41AI102507-01
Award Amount: $154,300.00
 

Abstract:

DESCRIPTION (provided by applicant): Carbapenemase-producing bacteria now threaten to undermine the efficacy of the carbapenems, long considered to be the most potent and reliable of the -lactam antibiotics. In Gram-negative microorganisms, in particular,the ability to produce class A serine carbapenemases, such as the plasmid-mediated KPC enzymes, or class B metallo-carbapenemases, such as the NDM-1 enzyme, can be combined with other resistance determinants, such as porin deletions and upregulated effluxsystems to generate a microorganism that is resistant to virtually all known antibiotic agents. In general, carbapenemases have extremely broad substrate specificity, hydrolyzing penicillins, cephalosporins, carbapenems, and often even monobactams. This project will systematically investigate structural alterations to the carbapenem scaffold that are predicted to improve stability to both serine and metallo-carbapenemases and also to improve antibacterial efficacy. A number of atypical structural modifications are proposed. If successful, these modifications might also be incorporated into other classes of bicyclic -lactam antibiotic to improve -lactamase stability. The biological evaluation of these newly modified carbapenems will involve tests of both inherent antibacterial efficacy as well as carbapenemase stability against a well-characterized series of both carbapenem-susceptible as well as carbapenem-resistant strains, including Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumanniiisolates. In addition, novel carbapenems possessing good antibacterial activity will be profiled for PBP binding potency and susceptibility to renal dehydropeptidases along with an in vitro DMPK investigation of metabolic stability. PUBLIC HEALTHRELEVANCE: Carbapenems are generally regarded as the most potent and dependable of the antibiotics. In order not to promote bacterial resistance, these agents are often reserved for the most serious and resistant bacterial infections. Despite this, however, some strains of bacteria have evolved carbapenem resistance, mainly by producing carbapenemases, which hydrolytically inactivate the antibiotics. This project is focused on the design of new carbapenems that will be carbapenemase resistant. These new agents would then be used to treat infections caused by highly resistant pathogens.

Principal Investigator:

Bret M. Benton
650-808-6158
bbenton@theravance.com

Business Contact:

Bret Benton
650-808-6158
bbenton@theravance.com
Small Business Information at Submission:

THERAVANCE, INC.
901 GATEWAY BLVD SOUTH SAN FRANCISCO, CA 94080-7024

EIN/Tax ID: 194326596
DUNS: N/A
Number of Employees: N/A
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
Research Institution Information:
SOUTHERN METHODIST UNIVERSITY
SOUTHERN METHODIST UNIVERSITY
6425 BOAZ LN, Suite 101
DALLAS, TX 75205-
Contact: