This project targets bacterial type IA topoisomerase for discovery of novel antibacterial drugs as countermeasure for multi-drug resistant bacterial pathogens, including gram negatives. Drugs that initiate cell killing by trapping the covalent cleavage complex formed by type IB and type IIA topoisomerases are widely used in current anti-cancer and anti-bacterial therapy. Accumulation of type IA topoisomerase cleavage complex can trigger rapid bacterial cell death via the oxidative cell death pathway but specific inhibitors of type IA bacterial topoisomerase I that can be developed into new antibacterial drugs remain to be discovered. The proposed research activities for the next funding period would develop and utilize rapid cell based applicable for HTS assay format to identify small molecule compounds that have antibacterial activity due to specific interaction with bacterial topoisomerase I. Inhibitors of bacterial topoisomerase I identified from screening would be analyzed biochemically for mechanism of action and structure activity relationship. Priority would be given to compounds with low toxicity that are active against gram negative Escherichia coli and Yersinia pestis in order to identify leads that can be used in development of therapeutic agents against gram negative pathogens. Bacterial proteins that process trapped topoisomerase cleavage complexes will be identified with genetic and biochemical experiments. The repair proteins involved may be useful new targets for combination therapy with antibiotics targeting both type IA and type IIA topoisomerases. Success in these proposed experiments would provide tools and leads for development of novel antibacterial drugs for the urgent public health problem of bacterial pathogens resistant to all current antibiotics.

Public Health Relevance

This project targets bacterial topoisomerase I enzyme for discovery of specific inhibitors. The proposed work would greatly aid the development of new antibacterial compounds against a novel target as part of the much needed arsenal to combat the global health problem of multi-drug drug resistant bacterial pathogens, including gram negatives.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI069313-09
Application #
8707935
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Mukhopadhyay, Suman
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Florida International University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33199
Feng, Li; Maddox, Marcus M; Alam, Md Zahidul et al. (2014) Synthesis, structure-activity relationship studies, and antibacterial evaluation of 4-chromanones and chalcones, as well as olympicin A and derivatives. J Med Chem 57:8398-420
Lin, Hao; Annamalai, Thirunavukkarasu; Bansod, Priyanka et al. (2013) Synthesis and antibacterial evaluation of anziaic acid and analogues as topoisomerase I inhibitors. Medchemcomm 4:
Aedo, Sandra; Tse-Dinh, Yuk-Ching (2013) SbcCD-mediated processing of covalent gyrase-DNA complex in Escherichia coli. Antimicrob Agents Chemother 57:5116-9
Cheng, Bokun; Cao, Shugeng; Vasquez, Victor et al. (2013) Identification of anziaic acid, a lichen depside from Hypotrachyna sp., as a new topoisomerase poison inhibitor. PLoS One 8:e60770
Narula, Gagandeep; Annamalai, Thirunavukkarasu; Aedo, Sandra et al. (2011) The strictly conserved Arg-321 residue in the active site of Escherichia coli topoisomerase I plays a critical role in DNA rejoining. J Biol Chem 286:18673-80
Liu, I-Fen; Sutherland, Jeanette H; Cheng, Bokun et al. (2011) Topoisomerase I function during Escherichia coli response to antibiotics and stress enhances cell killing from stabilization of its cleavage complex. J Antimicrob Chemother 66:1518-24
Zhang, Zhongtao; Cheng, Bokun; Tse-Dinh, Yuk-Ching (2011) Crystal structure of a covalent intermediate in DNA cleavage and rejoining by Escherichia coli DNA topoisomerase I. Proc Natl Acad Sci U S A 108:6939-44
Sutherland, Jeanette H; Tse-Dinh, Yuk-Ching (2010) Analysis of RuvABC and RecG involvement in the escherichia coli response to the covalent topoisomerase-DNA complex. J Bacteriol 192:4445-51
Liu, I-Fen; Annamalai, Thirunavukkarasu; Sutherland, Jeanette H et al. (2009) Hydroxyl radicals are involved in cell killing by the bacterial topoisomerase I cleavage complex. J Bacteriol 191:5315-9
Cheng, Bokun; Annamalai, Thirunavukkarasu; Sorokin, Elena et al. (2009) Asp-to-Asn substitution at the first position of the DxD TOPRIM motif of recombinant bacterial topoisomerase I is extremely lethal to E. coli. J Mol Biol 385:558-67

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