Abstract
Objectives: The present study explores the potential of known peptide deformylase (PDF) inhibitors as chemotherapeutic agents against experimental tuberculosis. Methods: Several PDF inhibitors like BB-3497, actinonin, 1, 10-phenanthroline, hydroxylamine hydrochloride, and galardin that have shown their potential against other bacteria were selected for their evaluation against Mycobacterium tuberculosis. Results: Based on in vitro studies, the minimum inhibitory concentration (MIC) of PDF inhibitors was found to be in the range of 0.2 74mg/L, and among different PDF inhibitors, BB-3497 and 1, 10-phenanthroline exhibited potent antimycobacterial activity. In addition PDF inhibitors exhibited bacteriostatic mode of inhibition. Ex vivo studies with BB-3497 and actinonin led to reduction of colony forming units (cfu) by almost 2 log10 units at their MIC concentration. Moreover, reduction of cfu by BB3497 was comparable to that of isoniazid. Under short course chemotherapy, BB-3497 was significantly active and comparable to isoniazid. Extended chemotherapy of 6 weeks with BB-3497 and actinonin revealed BB-3497 to be more potent under in vivo condition. Interestingly, BB-3497 and actinonin exhibited synergism with isoniazid and rifampicin under in vitro conditions and during chemotherapy of murine tuberculosis. Conclusions: Peptide deformylase inhibitors like BB-3497 and actinonin showed their efficacy against Mycobacterium tuberculosis under in vitro, ex vivo and in vivo conditions and BB-3497 was found to be the most efficacious inhibitor. Thus PDF from M. tuberculosis appears to be an attractive target for development of new antibiotics against tuberculosis.
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