Research in the Sarathy Lab
Dr. Sarathy’s research focuses on applying site-of-disease pharmacokinetic-pharmacodynamic (PK-PD) concepts to provide a pharmacological rationale for tuberculosis treatment efficacy. Mycobacterium tuberculosis (MTB) is a highly successful pathogen because it is well adapted to surviving in diverse host microniches with variable vasculature and distinct environmental conditions. Its ability to go into a nonreplicating drug persistent (NRP) state in response to stresses encountered within the host is a major impediment to curing the disease. The necrotic core of tuberculous lesions and cavities, commonly referred to as caseum, are reservoirs of extracellular bacteria that are recalcitrant to antibiotic treatment. Furthermore, suboptimal drug distribution in the non-vascularized caseous compartment results in pockets of subinhibitory drug concentrations and increased chances of emergence of resistant mutants. Effective eradication of this subpopulation using multidrug regimens promises to shorten the duration of tuberculosis chemotherapy and prevent disease relapse.
The Sarathy lab leverages a fully integrated mass spectrometry bioanalytical platform and biosafety level 3 facilities at CDI to study drug metabolism and pharmacokinetics (DMPK) properties of existing TB drugs and compounds in preclinical development. This work is enabled by lesion-centric PK studies in several animal models of TB infection. The coupling of laser capture microdissection (LCM) to liquid chromatography –tandem mass spectrometry (LC-MS/MS) analysis supports the detailed spatial and temporal resolution of drug distribution in TB granulomas.
Dr. Sarathy has also developed a series of in vitro assays that predict drug penetration in lung granulomas and drug potency against persistent subpopulations of MTB. Her study of MTB in caseum and infected macrophages allows for the incorporation of valuable lesion-centric PD measurements into translational models. Altogether, these tools enable her to interrogate host-bacteria-drug dynamics at the site of action.
The Sarathy lab continues to work closely with Dr. Dartois and accomplished medicinal chemists, microbiologists, pharmacologists and PK modelers from pharmaceutical companies and academic institutions to design better anti-infectives. The group’s work supports the rational prioritization of drug combinations for treatment-shortening TB regimen development.