A Mycobacteria-Specific Prodrug to Overcome Phenotypic AMR in <i>Mycobacterium tuberculosis</i>
Most front-line tuberculosis (TB) drugs are ineffective against hypoxic nonreplicating <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), 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 <i>Mtb</i>. 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 <i>Mtb</i> and significantly enhanced lethality in nonreplicating <i>Mtb</i>. Drug accumulation studies confirmed a modest but significant increase in MXF levels in nonreplicating <i>Mtb</i> 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 <i>Mtb</i>.
Authors
- Jennifer S. Hirschi (ORCID: https://orcid.org/0000-0002-3470-0561)
- Piyali Mukherjee (ORCID: https://orcid.org/0000-0002-3681-2559)
- Abdul Akhir (ORCID: https://orcid.org/0000-0002-7892-4997)
- Harinath Chakrapani (ORCID: https://orcid.org/0000-0002-7267-0906)
- Sharath Chandra Mallojjala (ORCID: https://orcid.org/0000-0003-0446-792X)
- Samsher Singh (ORCID: https://orcid.org/0000-0001-7075-931X)
- Grace Kaul (ORCID: https://orcid.org/0000-0002-2820-9573)
- Shalini Birua (ORCID: https://orcid.org/0000-0003-3603-3499)
- Amit Singh (ORCID: https://orcid.org/0000-0001-6761-1664)
- Sidharth Chopra (ORCID: https://orcid.org/0000-0001-8823-6074)
- Chetan Gadgil (ORCID: https://orcid.org/0000-0002-1728-0796)
- T. Anand Kumar
- Aparna Ramachandran (ORCID: https://orcid.org/0000-0002-4281-0357)
Institutions
- Binghamton University (US)
- Indian Institute of Science Education and Research Kolkata (IN)
- Indian Institute of Science Education and Research Mohali (IN)
- Institute of Genomics and Integrative Biology (IN)
- Indian Institute of Science Education and Research Pune (IN)
- Central Drug Research Institute (IN)
- Indian Institute of Science Education and Research, Bhopal (IN)
- National Chemical Laboratory (IN)
- Indian Institute of Science Education and Research Berhampur (IN)
- Indian Institute of Science Education and Research, Tirupati (IN)
- Institute of Cell Biology (UA)
- Indian Institute of Science Bangalore (IN)
- Academy of Scientific and Innovative Research (IN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-12-01
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01848
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 0.00