Altered expression profile of mycobacterial surface glycopeptidolipids following treatment with the antifungal azole inhibitors econazole and clotrimazole.
The azole antifungal drugs econazole and clotrimazole are known cytochrome P450 enzyme inhibitors. This study shows that these drugs are potent inhibitors of mycobacterial growth and are more effective against Mycobacterium smegmatis than isoniazid and ethionamide, two established anti-mycobacterial drugs. Several non-tuberculous mycobacteria, including the pathogenic members of the Mycobacterium avium-intracellulare complex (MAC) and the fast-growing saprophytic organism M. smegmatis, produce an array of serovar-specific (ss) and non-serovar-specific (ns) glycopeptidolipids (GPLs). GPL biosynthesis has been investigated for several years but has still not been fully elucidated. The authors demonstrate here that econazole and clotrimazole inhibit GPL biosynthesis in M. smegmatis. In particular, clotrimazole inhibits all four types of nsGPLs found in M. smegmatis, suggesting an early and common target within their biosynthetic pathway. Altogether, the data suggest that an azole-specific target, most likely a cytochrome P450, may be involved in the hydroxylation of the N-acyl chain in GPL biosynthesis. Azole antifungal drugs and potential derivatives could represent an interesting new range of anti-mycobacterial drugs, especially against opportunistic human pathogens including MAC, M. scrofulaceum, M. peregrinum, M. chelonae and M. abscessus.
Burguière
Adeline
A
School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Hitchen
Paul G
PG
Department of Biological Sciences, Imperial College, London, SW7 2AZ, UK.
Dover
Lynn G
LG
School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Dell
Anne
A
Department of Biological Sciences, Imperial College, London, SW7 2AZ, UK.
Besra
Gurdyal S
GS
School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
D000995:Antitubercular Agents / Q000494:pharmacology; D002473:Cell Wall / Q000737:chemistry*; D003022:Clotrimazole / Q000494:pharmacology*; D004464:Econazole / Q000494:pharmacology*; D005000:Ethionamide / Q000494:pharmacology; D006017:Glycolipids / Q000032:analysis*; D006020:Glycopeptides / Q000032:analysis*; D007538:Isoniazid / Q000494:pharmacology; D015394:Molecular Structure; D009161:Mycobacterium / Q000737:chemistry / Q000187:drug effects*; D009162:Mycobacterium avium / Q000187:drug effects; D020102:Mycobacterium smegmatis / Q000187:drug effects
D000995:Antitubercular Agents; D006017:Glycolipids; D006020:Glycopeptides; D004464:Econazole; D003022:Clotrimazole; D005000:Ethionamide; D007538:Isoniazid