Identifying and Tackling Emergent Vulnerability in Drug-Resistant Mycobacteria

The
global mechanisms and associated molecular alterations that occur
in drug-resistant mycobacteria are poorly understood. To address this,
we obtain genomics data and then construct a genome-scale response
network in isoniazid-resistant Mycobacterium smegmatis and apply a network-mining algorithm. Through this, we decipher
global alterations in an unbiased manner and identify emergent vulnerabilities
in resistant bacilli, of which redox response was prominent. Using
phenotypic profiling, we find that resistant bacilli exhibit collateral
sensitivity to several compounds that block antioxidant responses.
We find that nanogram/milliliter concentrations of ebselen, vancomycin,
and phenylarsine oxide, in combination with isoniazid, are highly
effective against Mycobacterium tuberculosis H37Rv and three clinical drug-resistant strains. Dynamic measurements
of cytoplasmic redox potential revealed a surprisingly diminished
capacity of clinical drug-resistant strains to counteract oxidative
stress, providing a mechanistic basis for efficient and synergistic
mycobactericidal activity of the drug combinations. Ebselen and vancomycin
appear to be promising repurposable drugs.