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Download Role of mycothiol in isoniazid resistance of Mycobacterium
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CIHR-UBC Strategic Training Program for Translational Research in Infectious Diseases Address: D452 – 2733 Heather Pavilion, Vancouver, BC V5Z 3J5 E-mail: [email protected] Voice: (604) 875-5063 Fax: (604) 875-4013 Website: http://cmdr.ubc.ca/trainingprogram Research Theme: Antibiotic resistance, novel therapeutic targets Sub-theme: Role of mycothiol in isoniazid resistance of Mycobacterium tuberculosis Principal Investigator: Dr. Yossef Av-Gay, PhD Telephone: Fax: E-mail: 604-875-4329 604- 875-4013 [email protected] Isoniazid (Inh) and ethionamide are both specific antimycobacterial drugs that share at least one site of action in mycolic acid biosynthesis. Inh is a prodrug which is oxidized by the bacterial catalase-peroxidase, KatG, to form reactive toxic species. Mutations in the katG gene confer an isoniazid resistance phenotype that was identified in the majority of Inh resistance clinical isolates. Mutations in proposed targets of isoniazid, inhA and kasA , also contribute to Inh resistance phenotype. Nevertheless, a considerable proportion of isoniazid resistant M. tuberculosis clinical isolates have “normal” katG, inhA and kasA genotype. Recently, we have shown that mutations in mycothiol biosynthesis genes cause isoniazid resistance in the nonpathogenic mycobacteria M. smegmatis. Mycothiol (MSH; AcCys-GlcN-Ins) is the major low molecular weight thiol produced by mycobacteria and serves analogous functions in mycobacteria to those of glutathione in gram-negative bacteria and eukaryotes. These functions include protection against oxidative damage and inactivation of electrophilic toxins. Distribution of mycothiol is limited to gram-positive actinomycetes and, of all the species tested; mycobacteria appear to generate the highest levels of mycothiol.Thus, mycothiol biosynthesis enzymes are considered as attractive drug targets for development of new therapeutics against TB. The main objective of the training research program is to train investigators in answering scientific questions while contributing to our understanding whether and to what extent mycothiol plays a role in determining an isoniazid resistance phenotype in the causative agent of TB, Mycobacterium tuberculosis. Updated: August 2003 Page 1
