title: Molecular basis for the exquisite sensitivity of Mycobacterium tuberculosis to isoniazid.
abstract: The exceptional sensitivity of Mycobacterium tuberculosis to isonicotinic acid hydrazide (INH) lacks satisfactory definition. M. tuberculosis is a natural mutant in oxyR, a central regulator of peroxide stress response. The ahpC gene, which encodes a critical subunit of alkyl hydroperoxide reductase, is one of the targets usually controlled by oxyR in bacteria. Unlike in mycobacterial species less susceptible to INH, the expression of ahpC was below detection limits at the protein level in INH-sensitive M. tuberculosis and Mycobacterium bovis strains. In contrast, AhpC was detected in several series of isogenic INH-resistant (INHr) derivatives. In a demonstration of the critical role of ahpC in sensitivity to INH, insertional inactivation of ahpC on the chromosome of Mycobacterium smegmatis, a species naturally insensitive to INH, dramatically increased its susceptibility to this compound. These findings suggest that AhpC counteracts the action of INH and that the levels of its expression may govern the intrinsic susceptibility of mycobacteria to this front-line antituberculosis drug.
authors.affiliation: Department of Microbiology, University of Texas Health Sciences Center at San Antonio 78284-7758, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Dhandayuthapani
authors.forename: V
authors.initials: V
authors.lastname: Deretic
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D001483:Base Sequence; D004268:DNA-Binding Proteins; D007438:Introns; D007538:Isoniazid / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009154:Mutation; D009161:Mycobacterium / Q000187:drug effects* / Q000235:genetics; D009163:Mycobacterium bovis / Q000187:drug effects / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics*; D010088:Oxidoreductases / Q000235:genetics; D010544:Peroxidases; D054464:Peroxiredoxins; D016133:Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics; D013045:Species Specificity; D014157:Transcription Factors / Q000235:genetics
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D010088:Oxidoreductases; D010544:Peroxidases; D054464:Peroxiredoxins; D007538:Isoniazid