Uday S. Ganapathy, Ph.D.

Assistant Member, Hackensack Meridian Health, Center for Discovery & Innovation
Assistant Professor, Hackensack Meridian Health School of Medicine, Department of Medical Sciences

Dr. Ganapathy is a microbiologist with 15 years of expertise in mycobacteriology, specializing in bacterial physiology, biochemistry, chemical biology, and, more recently, antimycobacterial drug discovery. He completed his PhD research in the lab of Dr. Sabine Ehrt at Weill Cornell Medical College in 2015. Following this, he undertook postdoctoral studies with Dr. Jessica Seeliger at Stony Brook University and Dr. Thomas Dick at Rutgers University and the Center for Discovery and Innovation (CDI). His PhD and early postdoctoral work focused on Mycobacterium tuberculosis (Mtb), using bacterial genetics and chemical biology approaches to investigate the pathogen.

In 2017, Dr. Ganapathy joined Dr. Dick’s group, where his research pivoted to non-tuberculous mycobacteria (NTM). He has led several successful NTM drug discovery projects, including a key collaboration with GlaxoSmithKline (GSK) to test TB-active lead compounds for efficacy against NTM. This collaboration resulted in the identification of novel drug classes and lead compounds for NTM drug development.

The clinical use of rifamycins in treating NTM lung disease is limited by intrinsic drug resistance. During his postdoctoral work in Dr. Dick’s lab, Dr. Ganapathy investigated the mechanisms of intrinsic rifamycin resistance in M. abscessus, the most common rapidly growing NTM pathogen. His work identified a dual mechanism of resistance in M. abscessus subsp. abscessus. Building on these findings, Dr. Ganapathy and Dr. Dick collaborated with Dr. Courtney C. Aldrich at the University of Minnesota to redesign rifamycins for enhanced activity against M. abscessus lung disease. This collaboration led to the development of C25-modified rifabutin analogs, which overcome intrinsic rifamycin resistance and are more than 200 times more potent against M. abscessus than rifampicin. Preclinical profiling of these candidates for NTM lung disease is ongoing.

Current Research

While TB cure rates have reached 85% globally, this progress is threatened by the emergence of drug resistance. Rifampicin-resistant TB (RR-TB) occurs due to acquired mutations in the drug’s target – the beta-subunit (RpoB) of bacterial RNA polymerase (RNAP) – that reduce drug-target binding. Multidrug-resistant TB (MDR-TB), defined as resistance to both rifampicin and isoniazid, has also emerged. MDR/RR-TB cannot be treated with first-line TB drug regimens. Instead, treatment has typically relied on second-line drugs that have worse side effects, require longer treatment times, and are increasingly ineffective due to drug resistance. Just 60% of global MDR/RR-TB cases can be cured with the highest mortality observed among HIV-coinfected patients, who require drugs that are compatible with anti-retroviral therapy (ART). Better drugs are needed to address the global health threat presented by MDR/RR-TB. Recently, we established a medicinal chemistry program to redesign rifamycins for Mycobacterium abscessus lung disease, synthesizing 150 novel C25-modified rifabutin analogs. We are actively exploring whether these analogs can overcome rifamycin resistance in MDR/RR-TB, potentially expanding the applications of C25-modified rifabutin analogs to include combatting TB drug-resistance. The proposed research has the potential to improve treatment options for patients with MDR/RR-TB, including those who are coinfected with HIV. In effect, this research has the potential to address emerging TB drug resistance and contribute to the global eradication of TB.

Selected Publications

Ganapathy US, Del Rio RG, Cacho-Izquierdo M, Ortega F, Lelièvre J, Barros-Aguirre D, Lindman M, Dartois V, Gengenbacher M, Dick T. A Leucyl-tRNA Synthetase Inhibitor with Broad-Spectrum Anti-Mycobacterial Activity. Antimicrob Agents Chemother. 2021 Apr 19;65(5):e02420-20
PMC8092876

Ganapathy US, Del Río RG, Cacho-Izquierdo M, Ortega F, Lelièvre J, Barros-Aguirre D, Aragaw WW, Zimmerman MD, Lindman M, Dartois V, Gengenbacher M, Dick T. A Mycobacterium tuberculosis NBTI DNA Gyrase Inhibitor Is Active against Mycobacterium abscessus. Antimicrob Agents Chemother. 2021 Nov 17;65(12):e0151421.
PMC8597734

Ganapathy US, Lan T, Krastel P, Lindman M, Zimmerman MD, Ho H, Sarathy JP, Evans JC, Dartois V, Aldrich CC, Dick T. Blocking Bacterial Naphthohydroquinone Oxidation and ADP-Ribosylation Improves Activity of Rifamycins against Mycobacterium abscessus. Antimicrob Agents Chemother. 2021 Aug 17;65(9):e0097821.
PMC8370238

Lan T*, Ganapathy US*, Sharma S, Ahn YM, Zimmerman M, Molodtsov V, Hegde P, Gengenbacher M, Ebright RH, Dartois V, Freundlich JS, Dick T, Aldrich CC. Redesign of Rifamycin Antibiotics to Overcome ADP-Ribosylation-Mediated Resistance. Angew Chem Int Ed Engl. 2022 Nov 7;61(45):e202211498.
PMC9633546

Ganapathy US*, Lan T*, Dartois V, Aldrich CC, Dick T. Blocking ADP-ribosylation expands the anti-mycobacterial spectrum of rifamycins. Microbiol Spectr. 2023 Sep 8;11(5):e0190023. PMC10580999

*Authors contributed equally to this work