Our laboratory studies the mechanisms by which phenotypic antimicrobial resistance (AMR) develops in Mycobacterium tuberculosis, the causative agent of tuberculosis. In contrast to genetic AMR, in which a bacterium acquires mutations in its own genome or genes from other bacteria that allow it and its progeny to survive and grow upon exposure to otherwise lethal concentrations of an antibiotic, phenotypic AMR is reversible and not attributable to a genetic change. It ensures transient survival during antibiotic exposure but is not stably inherited by the progeny of surviving cells such that populations that regrow from survivors of an antibiotic remain susceptible to that antibiotic. In a clinical context, phenotypic AMR prolongs treatment time, causes treatment failure and infection relapse, and fosters the emergence of genetic resistance.
Our work has numerous objectives:
- From a fundamental standpoint, our research activities will identify pathways that are important for the development of phenotypic AMR.
- From a translational perspective, understanding how persisters arise will position us to develop screening tests to identify novel compounds that prevent phenotypic AMR.
- Probing the relationship between phenotypic and genetic AMR will allow us to develop tools to predict the emergence of genetic resistance in treated patients to help guide formulation and administration of multi-drug regimens.
After completing my PhD in the laboratory of Dr. Mamadou Daffé at the Institute of Pharmacology and Structural Biology in 2009 in Toulouse, France, I joined the laboratory of Dr. Carl Nathan at Weill Cornell Medicine in New York, USA, as a postdoctoral fellow (2009-2014), an instructor (2014-2017) and an assistant professor (2017-2018). This experience spurred a continued interest in approaching TB research through multi-disciplinary approaches—spanning microbiology, biochemistry, genetics, structural biology, time-lapse and super-resolution fluorescence photomicroscopy and quantification of observed phenotypes using computational tools.
et al., 2021, Multiform antimicrobial resistance from a metabolic mutation, Science Advances, Vol:7, ISSN:2375-2548, Pages:1-17
et al., 2020, Nonredundant functions of Mycobacterium tuberculosis chaperones promote survival under stress, Molecular Microbiology, Vol:115, ISSN:0950-382X, Pages:272-289
Schrader SM, Vaubourgeix J, Nathan C, 2020, Biology of antimicrobial resistance and approaches to combat it, Science Translational Medicine, Vol:12, ISSN:1946-6234
et al., 2019, Persistent mycobacterium tuberculosis infection in mice requires PerM for successful cell division, Elife, Vol:8, ISSN:2050-084X, Pages:1-21
et al., 2019, Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition (vol 363, eaau8959, 2019), Science, Vol:364, ISSN:0036-8075