Isoniazid is one of the most effective antituberculosis drugs, yet its precise mechanism of action is still controversial. Using specialized linkage transduction, a single point mutation allele (S94A) within the putative target gene inhA was transferred in Mycobacterium tuberculosis. The inhA(S94A) allele was sufficient to confer clinically relevant levels of resistance to isoniazid killing and inhibition of mycolic acid biosynthesis. This resistance correlated with the decreased binding of the INH-NAD inhibitor to InhA, as shown by enzymatic and X-ray crystallographic analyses, and establishes InhA as the primary target of isoniazid action in M. tuberculosis.
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We gratefully acknowledge G. Morlock for sending us the DNA from the INH-resistant clinical isolate carrying the inhA(S94A) mutation. L. Kremer is supported by a grant from the Centre National de la Recherche Scientifique (ATIP “Microbiologie Fondamentale”). J.C.S. acknowledges the Robert A. Welch Foundation grant A-0015. We also acknowledge support for this work from US National Institutes of Health grants AI43268 and AI46669, and from the Structural Genomics Project grant 1P50GM6241. We also thank G. Hatfull for careful reading of this manuscript.
The authors declare no competing financial interests.
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