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)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI069313-06
Application #
8186092
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Mukhopadhyay, Suman
Project Start
2006-02-01
Project End
2012-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
6
Fiscal Year
2011
Total Cost
$402,500
Indirect Cost
Name
New York Medical College
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Banda, Srikanth; Cao, Nan; Tse-Dinh, Yuk-Ching (2017) Distinct Mechanism Evolved for Mycobacterial RNA Polymerase and Topoisomerase I Protein-Protein Interaction. J Mol Biol 429:2931-2942
Yu, Xufen; Zhang, Mingming; Annamalai, Thirunavukkarasu et al. (2017) Synthesis, evaluation, and CoMFA study of fluoroquinophenoxazine derivatives as bacterial topoisomerase IA inhibitors. Eur J Med Chem 125:515-527
Tan, Kemin; Cao, Nan; Cheng, Bokun et al. (2016) Insights from the Structure of Mycobacterium tuberculosis Topoisomerase I with a Novel Protein Fold. J Mol Biol 428:182-193
Sandhaus, Shayna; Taylor, Rosella; Edwards, Tiffany et al. (2016) A novel copper(II) complex identified as a potent drug against colorectal and breast cancer cells and as a poison inhibitor for human topoisomerase II?. Inorg Chem Commun 64:45-49
Banda, Srikanth; Tiwari, Purushottam Babu; Darici, Yesim et al. (2016) Investigating direct interaction between Escherichia coli topoisomerase I and RecA. Gene 585:65-70
Sandhaus, Shayna; Annamalai, Thirunavukkarasu; Welmaker, Greg et al. (2016) Small-Molecule Inhibitors Targeting Topoisomerase I as Novel Antituberculosis Agents. Antimicrob Agents Chemother 60:4028-36
Cheng, Bokun; Annamalai, Thirunavukkarasu; Sandhaus, Shayna et al. (2015) Inhibition of Zn(II) binding type IA topoisomerases by organomercury compounds and Hg(II). PLoS One 10:e0120022
Tse-Dinh, Yuk-Ching (2015) Targeting bacterial topoisomerase I to meet the challenge of finding new antibiotics. Future Med Chem 7:459-71
Yang, Jenny; Annamalai, Thirunavukkarasu; Cheng, Bokun et al. (2015) Antimicrobial Susceptibility and SOS-Dependent Increase in Mutation Frequency Are Impacted by Escherichia coli Topoisomerase I C-Terminal Point Mutation. Antimicrob Agents Chemother 59:6195-202
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

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