Journal
ACS INFECTIOUS DISEASES
Volume 2, Issue 9, Pages 592-607Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.6b00004
Keywords
collateral sensitivity; antioxidant responses; drug resistance mechanisms; genome-scale networks; systems biology; drug repurposing
Categories
Funding
- Department of Biotechnology (DBT), Government of India
- Wellcome DBT India Alliance grant [WT-DBT/500034-Z-09-Z]
- Department of Biotechnology (DBT) Grant [BT/PR5020/MED/29/1454/2012]
- DBT-IISc Partnership Program for Advanced Research in Biological Sciences, India [22-0905-0006-05-436]
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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 genomescale 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.
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