| Autor: |
Kumar TA; Department of Chemistry, Indian Institute of Science Education and Research (IISER), Pune, India., Birua S; Division of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India., SharathChandra M; Department of Chemistry, Binghamton University, New York, USA., Mukherjee P; Division of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India., Singh S; Division of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India., Kaul G; Division of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, Janakipuram Extension, Sitapur Road, Lucknow-226031, Uttar Pradesh, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India., Akhir A; Division of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, Janakipuram Extension, Sitapur Road, Lucknow-226031, Uttar Pradesh, India., Chopra S; Division of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, Janakipuram Extension, Sitapur Road, Lucknow-226031, Uttar Pradesh, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India., Hirschi J; Department of Chemistry, Binghamton University, New York, USA., Singh A; Division of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India., Chakrapani H; Department of Chemistry, Indian Institute of Science Education and Research (IISER), Pune, India. |
| Abstrakt: |
Most front-line tuberculosis drugs are ineffective against hypoxic non-replicating drug-tolerant Mycobacterium tuberculosis ( Mtb ) contributing to phenotypic antimicrobial resistance (AMR). This is largely due to the poor permeability in the thick and waxy cell wall of persister cells, leading to diminished drug accumulation and reduced drug-target engagement. Here, using an "arm-to-disarm" prodrug approach, we demonstrate that non-replicating Mtb persisters can be sensitized to Moxifloxacin (MXF), a front-line TB drug. We design and develop a series of nitroheteroaryl MXF prodrugs that are substrates for bacterial nitroreductases (NTR), a class of enzymes that are over-expressed in hypoxic Mtb . Enzymatic activation involves electron-transfer to the nitroheteroaryl compound followed by protonation via water that contributes to the rapid cleavage rate of the protective group by NTR to produce the active drug. Phenotypic and genotypic data are fully consistent with MXF-driven lethality of the prodrug in Mtb with the protective group being a relatively innocuous bystander. The prodrug increased intracellular concentrations of MXF than MXF alone and is more lethal than MXF in non-replicating persisters. Hence, arming drugs to improve permeability, accumulation and drug-target engagement is a new therapeutic paradigm to disarm phenotypic AMR. |
