The present application addresses the general problem of antibiotic resistance, in particular antibiotic-resistant tuberculosis (TB). The long-term goal of this research program is to develop new DNA gyrase inhibitors that are highly effective anti-tuberculosis (TB) agents with susceptible, multidrug-resistant, extensively drug- resistant, and completely drug-resistant forms of the disease. The specific goal of the present application is to develop a novel anti-mutant strategy for identifying lead antibacterial agents that will severely restrict the emergence of resistant mutants and to exploit the strategy to specifically identify anti-mutant gyrase inhibitors that are active against wild-type and quinolone-resistant mutants of M. tuberculosis. The anti-mutant strategy is based on the central hypothesis that new antibiotics having a closed or very narrow mutant selection window will severely restrict the rate at which resistant mutants emerge. Such antibiotics are expected to have increased clinical utility and longevity of use. Preliminary studies show that anti-mutant activity of new gyrase inhibitors does narrow the mutant selection window and restricts the recovery of induced mutants.
Three specific aims have been developed to integrate medicinal chemistry, microbiology, biochemistry and molecular modeling studies into a new anti-mutant strategy and to identify lead structures for development as effective anti-TB agents.
In Aims 1 and 2 we will develop new dione-class and C-7 aryl-quinolone-class agents that are active against wild-type cells, known quinolone-resistant gyrase mutants, and induced mutants generated against progenitor compounds within each class. In a third aim we will exploit two different models for agents binding to gyrase to identify and characterize new types of anti-mutant gyrase inhibitors. The expected outcome of this work is the generation of new lead gyrase inhibitors that exhibit a narrow mutant selection window and severely restrict the recovery of resistant mutants. Successful completion of these studies will provide a general framework for obtaining agents with excellent anti-mutant activity. The framework is expected to apply to many other structural and mechanistic antibiotic classes.

Public Health Relevance

Antibiotic resistance has been recognized for more than a decade as a major threat to public health in the US and elsewhere;patients are now dying from once-treatable infections, and few new compounds are in the drug pipeline. Developing a new approach and new criteria for creating novel antibiotics that will restrict the emergence of resistant bacteria will lead to more effective, longer-lived compounds. Application of the ideas to tuberculosis will be significant because on a global basis tuberculosis kills more people than any other infectious disease and because drug-resistant tuberculosis is growing in prevalence.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI087671-05
Application #
8645595
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Boyce, Jim P
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Iowa
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Malik, Muhammad; Mustaev, Arkady; Schwanz, Heidi A et al. (2016) Suppression of gyrase-mediated resistance by C7 aryl fluoroquinolones. Nucleic Acids Res 44:3304-16
Oppegard, Lisa M; Schwanz, Heidi A; Towle, Tyrell R et al. (2016) Fluoroquinolones stimulate the DNA cleavage activity of topoisomerase IV by promoting the binding of Mg(2+) to the second metal binding site. Biochim Biophys Acta 1860:569-75
Aldred, Katie J; Blower, Tim R; Kerns, Robert J et al. (2016) Fluoroquinolone interactions with Mycobacterium tuberculosis gyrase: Enhancing drug activity against wild-type and resistant gyrase. Proc Natl Acad Sci U S A 113:E839-46
Blower, Tim R; Williamson, Benjamin H; Kerns, Robert J et al. (2016) Crystal structure and stability of gyrase-fluoroquinolone cleaved complexes from Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 113:1706-13
Liu, Yuanli; Zhou, Jinan; Qu, Yilin et al. (2016) Resveratrol Antagonizes Antimicrobial Lethality and Stimulates Recovery of Bacterial Mutants. PLoS One 11:e0153023
Long, Quanxin; Du, Qinglin; Fu, Tiwei et al. (2015) Involvement of Holliday junction resolvase in fluoroquinolone-mediated killing of Mycobacterium smegmatis. Antimicrob Agents Chemother 59:1782-5
Aldred, Katie J; Schwanz, Heidi A; Li, Gangqin et al. (2015) Activity of quinolone CP-115,955 against bacterial and human type II topoisomerases is mediated by different interactions. Biochemistry 54:1278-86
Malik, Muhammad; Li, Liping; Zhao, Xilin et al. (2014) Lethal synergy involving bicyclomycin: an approach for reviving old antibiotics. J Antimicrob Chemother 69:3227-35
Aldred, Katie J; Breland, Erin J; McPherson, Sylvia A et al. (2014) Bacillus anthracis GrlAV96A topoisomerase IV, a quinolone resistance mutation that does not affect the water-metal ion bridge. Antimicrob Agents Chemother 58:7182-7
Drlica, Karl; Mustaev, Arkady; Towle, Tyrell R et al. (2014) Bypassing fluoroquinolone resistance with quinazolinediones: studies of drug-gyrase-DNA complexes having implications for drug design. ACS Chem Biol 9:2895-904

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