Sampson AE, Barry CE; American Society for Microbiology. General Meeting.
Abstr Gen Meet Am Soc Microbiol. 1999 May 30-Jun 3; 99: 635 (abstract no. U-9).
NIH, NIAID, Rockville, MD.
Ethionamide (2-ethyl thioisonicotinamide) is an efficacious, relatively non-toxic, second line antituberculosis drug, which has been in use since the 1960s. Its MIC for Mycobacterium tuberculosis can range from 0.5 to 5.0 micrograms ml-1 and it leads to a loss of acid fastness, with evidence to support an assumed target of action as the inhibition of mycolic acid biosynthesis. Synthetic chemical conversion of the ethionamide thioamide group to a sulfoxide lowers the drug MIC for M. Smegmatis and M. Aberculosis. We have isolated a gene containing a putative regulator for a p450 monooxygenase, which when over expressed on a multi- copy plasmid, confers resistance to ethionamide and its sulfoxide. The plasmid in an M. Smegmatis clone does not confer resistance to the anti-tuberculosis drug isoniazid but confers resistance to other drugs, an example of which is thiacetazone. Thiacetazone (p-acetylaminobenzaldehyde thiosemicarbazone), a relatively toxic but inexpensive, commonly used tuberculostatic drug in the developing world, also contains a thioamide group. Clinical cross-resistance between ethionamide and thiacetazone in M. Tuberculosis strains has been noted in the literature for many years. Possible mycobacterial metabolites of ethionamide and 14C- radiolabeled ethionamide have been synthesized, all of which have been used to support a postulated model for the activation and metabolism of ethionamide and related thioamides.
Publication Types:
Keywords:
- Antitubercular Agents
- Ethionamide
- Isoniazid
- Microbial Sensitivity Tests
- Mycobacterium
- Mycobacterium tuberculosis
- Mycolic Acids
- Thioacetazone
- Thioamides
- Tuberculosis
- biosynthesis
- metabolism
Other ID:
UI: 102195768
From Meeting Abstracts