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)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Parker, Tina M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard Medical School
United States
Zip Code
Gong, Lingyan; Ouyang, Wei; Li, Zirui et al. (2018) Direct numerical simulation of continuous lithium extraction from high Mg2+/Li+ ratio brines using microfluidic channels with ion concentration polarization. J Memb Sci 556:34-41
Hicks, Nathan D; Yang, Jian; Zhang, Xiaobing et al. (2018) Clinically prevalent mutations in Mycobacterium tuberculosis alter propionate metabolism and mediate multidrug tolerance. Nat Microbiol 3:1032-1042
Linger, Yvonne; Knickerbocker, Christopher; Sipes, David et al. (2018) Genotyping Multidrug-Resistant Mycobacterium tuberculosis from Primary Sputum and Decontaminated Sediment with an Integrated Microfluidic Amplification Microarray Test. J Clin Microbiol 56:
Sakatos, Alexandra; Babunovic, Gregory H; Chase, Michael R et al. (2018) Posttranslational modification of a histone-like protein regulates phenotypic resistance to isoniazid in mycobacteria. Sci Adv 4:eaao1478
Thakore, Nitu; Norville, Ryan; Franke, Molly et al. (2018) Automated TruTip nucleic acid extraction and purification from raw sputum. PLoS One 13:e0199869
Thakore, Nitu; Garber, Steve; Bueno, Arial et al. (2018) A bench-top automated workstation for nucleic acid isolation from clinical sample types. J Microbiol Methods 148:174-180
Ouyang, Wei; Han, Jongyoon; Wang, Wei (2017) Enabling electrical biomolecular detection in high ionic concentrations and enhancement of the detection limit thereof by coupling a nanofluidic crystal with reconfigurable ion concentration polarization. Lab Chip 17:3772-3784
Gong, Lingyan; Ouyang, Wei; Li, Zirui et al. (2017) Force fields of charged particles in micro-nanofluidic preconcentration systems. AIP Adv 7:125020
Yadon, Adam N; Maharaj, Kashmeel; Adamson, John H et al. (2017) A comprehensive characterization of PncA polymorphisms that confer resistance to pyrazinamide. Nat Commun 8:588
Calderón, R I; Velásquez, G E; Becerra, M C et al. (2017) Prevalence of pyrazinamide resistance and Wayne assay performance analysis in a tuberculosis cohort in Lima, Peru. Int J Tuberc Lung Dis 21:894-901

Showing the most recent 10 out of 19 publications