Synergistic activities of antituberculous drugs with cerulenin and trans-cinnamic acid against Mycobacterium tuberculosis.
The recent upsurge in the incidence of tuberculosis with significant emergence of multidrug-resistant cases has focused on the priority of discovering effective new drugs and on the strategies to augment the potential of existing drugs against Mycobacterium tuberculosis. In the present study, we investigated cerulenin and trans-cinnamic acid, which have recently been shown to augment the activity of various antibiotics against Mycobacterium avium [Antimicrob. Agents Chemother. 38 (1994) 2287-2295], to enhance the activity of isoniazid, rifampin, ofloxacin, amikacin and clofazimine against M. tuberculosis. The synergy observed was compared with identical combinations using ethambutol, a cell wall-inhibiting drug used in standard antituberculous chemotherapy. The results showed that ethambutol resulted in synergistic activity in 12/30 drug combinations, as compared to 15/36 for cerulenin and 101/18 for trans-cinnamic acid. This increase in drug activity was even observed with drug-resistant isolates. Use of novel antimicrobials and understanding of their mechanisms of action may be an effective strategy to determine previously undescribed targets for future drug development.
Unité de la Tuberculose et des Mycobactéries, Institut Pasteur, Pointe à Pitre, Guadeloupe. rastogi@ipagua.gp
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Rastogi
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Goh
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Horgen
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Barrow
D000904:Antibiotics, Antitubercular / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000494:pharmacology*; D002569:Cerulenin / Q000494:pharmacology*; D002934:Cinnamates / Q000494:pharmacology*; D015169:Colony Count, Microbial; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004977:Ethambutol / Q000494:pharmacology; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy
D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D002934:Cinnamates; D002569:Cerulenin; D004977:Ethambutol