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TB Notes Newsletter

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No. 3, 2010

Updates from the Mycobacteriology Laboratory Branch

Cross Resistance Among the Injectables: Is It Always Guaranteed?

One of the main areas of research of the Applied Research Team within the Mycobacteriology Laboratory Branch is to elucidate the molecular mechanisms of drug resistance of Mycobacterium tuberculosis. Resistance to the first-line drugs has been studied extensively, and the majority of the mutations and affected genes are known.  However, less is known regarding the second-line drugs used to treat drug-resistant TB.  Understanding the molecular basis of resistance in M. tuberculosis is key to developing molecular tests that can rapidly identify drug-resistant strains. An earlier diagnosis could help prevent the spread of TB and allow the treatment of patients with an effective drug regimen in a timelier manner.

We are currently investigating the molecular basis of resistance to the injectable drugs (e.g., kanamycin, amikacin, and capreomycin) and fluoroquinolones used to treat drug- resistant disease, and we recently published related findings in Proceedings of the National Academy of Sciences describing a novel mechanism of kanamycin resistance in M. tuberculosis.  We identified mutations in the promoter region of a gene encoding an aminoglycoside acetyltransferase (eis, Rv2416c); these mutations ultimately increase the level of this protein that is able to modify and inactivate kanamycin, resulting in drug resistance.  A unique feature of this mechanism is the lack of cross-resistance to the other injectables, which is common for mutations in the gene encoding the 16s rRNA (rrs).  Therefore, strains harboring specific eis promoter mutations are resistant to kanamycin but are susceptible to amikacin and capreomycin.  Based on these results, the Clinical and Laboratories Standard Institute document M24-A, Susceptibility Testing of Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard, is being revised to recommend testing kanamycin and amikacin independently instead of using kanamycin as the class representative.  This new testing strategy could help prevent the removal of amikacin from an effective drug regimen for patients infected with strains of M. tuberculosis harboring eis mutations.

 —Submitted by James E. Posey, PhD
Div of TB Elimination


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