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

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