OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice.

Abstract

BACKGROUND:

Tuberculosis (TB) is still a leading cause of death worldwide. Almost a third of the world's population is infected with TB bacilli, and each year approximately 8 million people develop active TB and 2 million die as a result. Today's TB treatment, which dates back to the 1970s, is long and burdensome, requiring at least 6 mo of multidrug chemotherapy. The situation is further compounded by the emergence of multidrug-resistant TB (MDR-TB) and by the infection's lethal synergy with HIV/AIDS. Global health and philanthropic organizations are now pleading for new drug interventions that can address these unmet needs in TB treatment.

METHODS AND FINDINGS:

Here we report OPC-67683, a nitro-dihydro-imidazooxazole derivative that was screened to help combat the unmet needs in TB treatment. The compound is a mycolic acid biosynthesis inhibitor found to be free of mutagenicity and to possess highly potent activity against TB, including MDR-TB, as shown by its exceptionally low minimum inhibitory concentration (MIC) range of 0.006-0.024 microg/ml in vitro and highly effective therapeutic activity at low doses in vivo. Additionally, the results of the post-antibiotic effect of OPC-67683 on intracellular Mycobacterium tuberculosis showed the agent to be highly and dose-dependently active also against intracellular M. tuberculosis H37Rv after a 4-h pulsed exposure, and this activity at a concentration of 0.1 microg/ml was similar to that of the first-line drug rifampicin (RFP) at a concentration of 3 microg/ml. The combination of OPC-67683 with RFP and pyrazinamide (PZA) exhibited a remarkably quicker eradication (by at least 2 mo) of viable TB bacilli in the lung in comparison with the standard regimen consisting of RFP, isoniazid (INH), ethambutol (EB), and PZA. Furthermore, OPC-67683 was not affected by nor did it affect the activity of liver microsome enzymes, suggesting the possibility for OPC-67683 to be used in combination with drugs, including anti-retrovirals, that induce or are metabolized by cytochrome P450 enzymes.

CONCLUSIONS:

We concluded that based on these properties OPC-67683 has the potential to be used as a TB drug to help combat the unmet needs in TB treatment.

• Authors: Makoto Matsumoto, Hiroyuki Hashizume, Tatsuo Tomishige, Masanori Kawasaki, Hidetsugu Tsubouchi, Hirofumi Sasaki, Yoshihiko Shimokawa, Makoto Komatsu
• Journal: PLoS medicine (PLoS Med) Vol. 3 Issue 11 Pg. e466 (Nov 2006) ISSN: 1549-1676 [Electronic] United States
• PMID: 17132069 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antitubercular Agents
• Mycolic Acids
• Nitroimidazoles
• OPC-67683
• Oxazoles

Topics

• Animals
• Antitubercular Agents (pharmacology, therapeutic use)
• Blood (microbiology)
• Cell Line
• Humans
• In Vitro Techniques
• Intracellular Membranes (microbiology)
• Macrophages (microbiology)
• Mammals
• Mice
• Microbial Sensitivity Tests
• Microsomes, Liver (microbiology)
• Mycobacterium (drug effects, metabolism)
• Mycobacterium bovis (drug effects, metabolism)
• Mycolic Acids (antagonists & inhibitors)
• Nitroimidazoles (pharmacology, therapeutic use)
• Oxazoles (pharmacology, therapeutic use)
• Treatment Outcome
• Tuberculosis (blood, drug therapy, prevention & control)