Abstract:
The aim of this proposal is to study and exploit the non-classical cross-linkages present in the peptidoglycan layer of bacteria. This layer is vital to the survival of bacilli and is maintained by linking peptide and glycan chains. One the most successful class of antibiotics in human clinical use, namely the ?-lactams and cephalosporins, targets the classical 4?3 linkages. The existing paradigm describes the peptidoglycan layer as a structure largely maintained by classical 4?3 linkages. Our recent studies of one of the most significant human pathogens, Mycobacterium tuberculosis (Mtb), has revealed that its peptidoglycan layer is composed of 3?3 (non-classical cross-links) and undergoes remodeling when the bacterium transitions from one growth phase to another. Other laboratories have recently identified this enzyme in bacteria such as E. coli and B. subtilis suggesting that this enzyme is widely present and vital for viability of bacteria. Emerging evidence from recent publications link remodeling of the peptidoglycan to contain 3?3 transpeptide bonds to adaptation during chronic phase of infection. In a short period of 2 years we have characterized a 3?3 transpeptidase and have now solved the molecular structure of the crystal containing native substrate. This proposal aims to develop and identify small molecules that mimic the substrate inhibit this novel transpeptidase activity. The inhibitor would be a promising new class of antibacterial drug Public Health Relevance: This proposal aims to investigate novel structures and molecules that are present in all important human bacterial pathogens. It is expected that findings from the proposed studies will lead to development of new interventions to kill bacteria. These drugs/anti-bacterials may be effective against a wide range of bacteria including those that are resistant to existing drugs.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
1DP2OD008459-01
Application #
8145918
Study Section
Special Emphasis Panel (ZGM1-NDIA-S (01))
Program Officer
Basavappa, Ravi
Project Start
2011-09-30
Project End
2016-06-30
Budget Start
2011-09-30
Budget End
2016-06-30
Support Year
1
Fiscal Year
2011
Total Cost
$2,430,000
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Kumar, Pankaj; Chauhan, Varsha; Silva, José Rogério A et al. (2017) Mycobacterium abscessus l,d-Transpeptidases Are Susceptible to Inactivation by Carbapenems and Cephalosporins but Not Penicillins. Antimicrob Agents Chemother 61:
Kumar, Pankaj; Kaushik, Amit; Lloyd, Evan P et al. (2017) Non-classical transpeptidases yield insight into new antibacterials. Nat Chem Biol 13:54-61
Njire, Moses; Wang, Na; Wang, Bangxing et al. (2017) Pyrazinoic Acid Inhibits a Bifunctional Enzyme in Mycobacterium tuberculosis. Antimicrob Agents Chemother 61:
Kaushik, Amit; Ammerman, Nicole C; Tasneen, Rokeya et al. (2017) In vitro and in vivo activity of biapenem against drug-susceptible and rifampicin-resistant Mycobacterium tuberculosis. J Antimicrob Chemother 72:2320-2325
Bianchet, Mario A; Pan, Ying H; Basta, Leighanne A Brammer et al. (2017) Structural insight into the inactivation of Mycobacterium tuberculosis non-classical transpeptidase LdtMt2 by biapenem and tebipenem. BMC Biochem 18:8
Kumar, Pankaj; Kaushik, Amit; Bell, Drew T et al. (2017) Mutation in an Unannotated Protein Confers Carbapenem Resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 61:
Mattoo, Rohini; Lloyd, Evan P; Kaushik, Amit et al. (2017) LdtMav2, a nonclassical transpeptidase and susceptibility of Mycobacterium avium to carbapenems. Future Microbiol 12:595-607
Makafe, Gaëlle Guiewi; Cao, Yuanyuan; Tan, Yaoju et al. (2016) Role of the Cys154Arg Substitution in Ribosomal Protein L3 in Oxazolidinone Resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 60:3202-6
Pelly, Shaaretha; Winglee, Kathryn; Xia, Fang Fang et al. (2016) REMap: Operon map of M. tuberculosis based on RNA sequence data. Tuberculosis (Edinb) 99:70-80
Kaushik, Amit; Heuer, Abigail M; Bell, Drew T et al. (2016) An evolved oxazolidinone with selective potency against Mycobacterium tuberculosis and gram positive bacteria. Bioorg Med Chem Lett 26:3572-6

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