2. Academic Validation
  3. A Mycobacteria-Specific Prodrug to Overcome Phenotypic AMR in Mycobacterium tuberculosis

A Mycobacteria-Specific Prodrug to Overcome Phenotypic AMR in Mycobacterium tuberculosis

  • J Med Chem. 2025 Dec 11;68(23):24935-24952. doi: 10.1021/acs.jmedchem.5c01848.
T Anand Kumar 1,  Shalini Birua 2,  Sharath Chandra Mallojjala 3,  Piyali Mukherjee 2,  Samsher Singh 2,  Grace Kaul 4 5,  Aparna Ramachandran 5 6,  Abdul Akhir 4,  Sidharth Chopra 4 5,  Chetan J Gadgil 5 6 7,  Jennifer S Hirschi 3,  Amit Singh 2,  Harinath Chakrapani 1
Affiliations

Affiliations

  • 1 Department of Chemistry, Indian Institute of Science Education and Research (IISER), Pune, Maharashtra 411 008, India.
  • 2 Division of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka 560 012, India.
  • 3 Department of Chemistry, Binghamton University, Binghamton, New York 13902, United States.
  • 4 Division of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, Janakipuram Extension, Sitapur Road, Lucknow, Uttar Pradesh 226031, India.
  • 5 Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
  • 6 CSIR-National Chemical Laboratory, Pune, Maharashtra 411008, India.
  • 7 CSIR-Institute of Genomics and Integrative Biology, New Delhi 110025, India.
PMID: 41324129 DOI: 10.1021/acs.jmedchem.5c01848
Abstract

Most front-line tuberculosis (TB) drugs are ineffective against hypoxic nonreplicating Mycobacterium tuberculosis (Mtb), largely due to poor permeability, leading to reduced drug accumulation and target engagement. To overcome this phenotypic antimicrobial resistance (AMR), we developed nitroheteroaryl prodrugs for Moxifloxacin (MXF), a front-line TB drug. These prodrugs are activated by Bacterial nitroreductases (NTR), which are overexpressed in hypoxic Mtb. NTR-mediated electron transfer and protonation facilitate rapid cleavage of the protective group, releasing active MXF. The lead prodrug exhibited comparable efficacy to MXF in replicating Mtb and significantly enhanced lethality in nonreplicating Mtb. Drug accumulation studies confirmed a modest but significant increase in MXF levels in nonreplicating Mtb treated with the prodrug, suggesting improved permeability. A mathematical model integrating growth and drug-killing kinetics further elucidated how permeability differences impact lethality. Together, these findings highlight enzyme-activated prodrugs as a promising strategy to address phenotypic AMR in Mtb.

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