Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves the target of isoniazid. Academic Article

abstract

• 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.

authors

• Sacchettini, James

published proceedings

• Nat Med

altmetric score

• 3

author list (cited authors)

• Vilchze, C., Wang, F., Arai, M., Hazbn, M. H., Colangeli, R., Kremer, L., ... Jacobs, W. R.

citation count

• 233

complete list of authors

• Vilchèze, Catherine||Wang, Feng||Arai, Masayoshi||Hazbón, Manzour Hernando||Colangeli, Roberto||Kremer, Laurent||Weisbrod, Torin R||Alland, David||Sacchettini, James C||Jacobs, William R

publication date

• September 2006

publisher

• Springer Nature  Publisher

published in

• Nature Medicine  Journal

keywords

• Antitubercular Agents
• Bacterial Proteins
• Crystallography, X-Ray
• Drug Resistance, Bacterial
• Isoniazid
• Mycobacterium Tuberculosis
• Mycolic Acids
• NAD
• Oxidoreductases
• Point Mutation

PubMed Central ID

• 16906155

Digital Object Identifier (DOI)

• 10.1038/nm1466

start page

• 1027

end page

• 1029

volume

• 12

issue

• 9

URL

• http://dx.doi.org/10.1038/nm1466