Antimycobacterial Muraymycins Isolated from Streptomyces sp. NRRL 30475 Using OSMAC and Precursor-Feeding Strategies

Three mutant strains of Streptomyces sp. NRRL 30471 were screened with eight different media based on “One Strain Many Compounds” (OSMAC) and precursor-feeding strategies. Five new muraymycins, D5–D9 (4–8), together with three known congeners were isolated and identified from Streptomyces sp. NRRL 30475 using an optimized BPM23A medium containing methionine, leucine, and arginine (each 1.5 g/L). Structures of new compounds were elucidated using HR-MS and NMR spectroscopic data. Muraymycin D6 (5) represents the first natural muraymycin with phosphorylation at the 3′-OH of the ribofuranoside moiety. Muraymycin D9 (8) features a unique dehydrocyclization of the carboxyl of a valine with the epicapreomycidine imide of the peptide moiety, forming an isopropyl hydantoin structure. Except for muraymycin D8 (7), which lacked the ribofuranose, all isolated muraymycins (1–6 and 8) displayed potent antimycobacterial activity against Mycolicibacterium smegmatis (MIC = 2–32 μg/mL). Specifically, the activities of 1–4 and 6 were even better than those of the positive control isoniazid (MIC = 16 μg/mL). Moreover, muraymycins D1, D2, D4, and D5 (1–4) had antimycobacterial effects against M. tuberculosis with MIC values in the range of 8–16 μg/mL. This finding highlights muraymycin nucleoside has potential for the development of antituberculosis antibiotics.