Discovery of Nosiheptide, Griseoviridin, and Etamycin as Potent Anti-Mycobacterial Agents against Mycobacterium avium Complex

Abstract

Mycobacterium avium complex (MAC) is a serious disease mainly caused by M. avium and M. intracellulare. Although the incidence of MAC infection is increasing worldwide, only a few agents are clinically used, and their therapeutic effects are limited. Therefore, new anti-MAC agents are needed. Approximately 6600 microbial samples were screened for new anti-mycobacterial agents that inhibit the growth of both M. avium and M. intracellulare, and two culture broths derived from marine actinomycete strains OPMA1245 and OPMA1730 had strong activity. Nosiheptide (1) was isolated from the culture broth of OPMA1245, and griseoviridin (2) and etamycin (viridogrisein) (3) were isolated from the culture broth of OPMA1730. They had potent anti-mycobacterial activity against M. avium and M. intracellulare with minimum inhibitory concentrations (MICs) between 0.024 and 1.56 μg/mL. In addition, a combination of 2 and 3 markedly enhanced the anti-mycobacterial activity against both M. avium and M. intracellulare. Furthermore, a combination 2 and 3 had a therapeutic effect comparable to that of ethambutol in a silkworm infection assay with M. smegmatis.

Keywords: Mycobacterium avium complex; antimycobacterial activity; etamycin; griseoviridin; marine-derived actinomycete.; microbial product; nontuberculous mycobacteria; nosiheptide; viridogrisein.

Figure 1

Structures of 1–3.

Figure 2

Therapeutic effects of 1 and 2/3 in the silkworm infection assay with M. smegmatis. Dose: ◊ 50 µg/larva for 1. ▲ 12.5 and ◆ 50 µg/larva for 2/3. ☐ control (no drug). ■ no infection with M. smegmatis. Experiments were performed twice to confirm reproducibility.