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.