title: Identifying and Tackling Emergent Vulnerability in Drug-Resistant Mycobacteria.
abstract: 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.
authors.affiliation: Department of Biochemistry, ‡Supercomputer Education and Research Centre, #Molecular Biophysics Unit, ΔMicrobiology and Cellular Biology, and ⊥Centre for Infectious Disease Research, Indian Institute of Science , Bangalore 560012, India.
authors.forename: Jyothi
authors.initials: J
authors.lastname: Padiadpu
authors.affiliation: Department of Biochemistry, ‡Supercomputer Education and Research Centre, #Molecular Biophysics Unit, ΔMicrobiology and Cellular Biology, and ⊥Centre for Infectious Disease Research, Indian Institute of Science , Bangalore 560012, India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Baloni
authors.affiliation: Department of Biochemistry, ‡Supercomputer Education and Research Centre, #Molecular Biophysics Unit, ΔMicrobiology and Cellular Biology, and ⊥Centre for Infectious Disease Research, Indian Institute of Science , Bangalore 560012, India.
authors.forename: Kushi
authors.initials: K
authors.lastname: Anand
authors.affiliation: Department of Biochemistry, ‡Supercomputer Education and Research Centre, #Molecular Biophysics Unit, ΔMicrobiology and Cellular Biology, and ⊥Centre for Infectious Disease Research, Indian Institute of Science , Bangalore 560012, India.
authors.forename: MohamedHusen
authors.initials: M
authors.lastname: Munshi
authors.affiliation: Department of Biochemistry, ‡Supercomputer Education and Research Centre, #Molecular Biophysics Unit, ΔMicrobiology and Cellular Biology, and ⊥Centre for Infectious Disease Research, Indian Institute of Science , Bangalore 560012, India.
authors.forename: Chandrani
authors.initials: C
authors.lastname: Thakur
authors.affiliation: Department of Biochemistry, ‡Supercomputer Education and Research Centre, #Molecular Biophysics Unit, ΔMicrobiology and Cellular Biology, and ⊥Centre for Infectious Disease Research, Indian Institute of Science , Bangalore 560012, India.
authors.forename: Abhilash
authors.initials: A
authors.lastname: Mohan
authors.affiliation: Department of Biochemistry, ‡Supercomputer Education and Research Centre, #Molecular Biophysics Unit, ΔMicrobiology and Cellular Biology, and ⊥Centre for Infectious Disease Research, Indian Institute of Science , Bangalore 560012, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Biochemistry, ‡Supercomputer Education and Research Centre, #Molecular Biophysics Unit, ΔMicrobiology and Cellular Biology, and ⊥Centre for Infectious Disease Research, Indian Institute of Science , Bangalore 560012, India.
authors.forename: Nagasuma
authors.initials: N
authors.lastname: Chandra
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D016680:Genome, Bacterial; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009165:Mycobacterium Infections, Nontuberculous / Q000382:microbiology*; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D014376:Tuberculosis / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D007538:Isoniazid
keywords: antioxidant responses; collateral sensitivity; drug repurposing; drug resistance mechanisms; genome-scale networks; systems biology