Drug-resistant tuberculosis is a serious public health threat. Diagnosis of drug-resistant strains presents a particularly urgent challenge, as such strains are responsible for an increasing burden of morbidity and mortality worldwide. Genome-wide scans that have revealed multiple genetic variants that are associated with drug resistance. The goal of this project is to identify and validate which ofthe resistance-associated mutations are causally connected to either high-level drug resistance or an increased risk of developing resistance. In addition, for selected mutations and agents, we plan to further explore the spectrum of potential mutations that either have not yet been found in clinical isolates or whose association with drug resistance is unclear. Specifically, we will construct isogenic strains containing resistance-associated mutations, producing strains with single point mutations in an otherwise wild type genetic background. We will determine the drug resistance phenotype of the resistance-associated mutations, and we will also predict mutations associated with resistance not yet seen in clinical isolates. Taken together these studies will lead to validated SNPs that will serve as the basis for much needed sequence-based diagnostic tests for tuberculosis.

Public Health Relevance

Drug resistant tuberculosis is a serious public health threat and more rapid diagnosis of drug resistant strains is desperately needed. The findings from this project will translate directly into validated bacterial genetic resistance-associated mutations, which will be the basis for sequenced-based diagnosis of drug resistance.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-LR-M (J1))
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Harvard University
United States
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Farhat, Maha R; Jacobson, Karen R; Franke, Molly F et al. (2016) Gyrase Mutations Are Associated with Variable Levels of Fluoroquinolone Resistance in Mycobacterium tuberculosis. J Clin Microbiol 54:727-33
Farhat, Maha R; Sultana, Razvan; Iartchouk, Oleg et al. (2016) Genetic Determinants of Drug Resistance in Mycobacterium tuberculosis and Their Diagnostic Value. Am J Respir Crit Care Med 194:621-30
Rock, Jeremy M; Lang, Ulla F; Chase, Michael R et al. (2015) DNA replication fidelity in Mycobacterium tuberculosis is mediated by an ancestral prokaryotic proofreader. Nat Genet 47:677-81
Farhat, M R; Mitnick, C D; Franke, M F et al. (2015) Concordance of Mycobacterium tuberculosis fluoroquinolone resistance testing: implications for treatment. Int J Tuberc Lung Dis 19:339-41
Farhat, Maha R; Shapiro, B Jesse; Sheppard, Samuel K et al. (2014) A phylogeny-based sampling strategy and power calculator informs genome-wide associations study design for microbial pathogens. Genome Med 6:101