Collismycin B

Five new nucleoside antibiotics, named streptcytosines A-E (1-5), and six known compounds, de-amosaminyl-cytosamine (6), plicacetin (7), bamicetin (8), amicetin (9), collismycin B (10), and SF2738 C (11), were isolated from a culture broth of Streptomyces sp. TPU1236A collected in Okinawa, Japan. The structures of new compounds were elucidated on the basis of their spectroscopic data (HRFABMS, IR, UV, and 2D NMR experiments including 1H-1H COSY, HMQC, HMBC, and NOESY spectra). Streptcytosine A (1) belonged to the amicetin group antibiotics, and streptcytosines B-E (2-5) were derivatives of de-amosaminyl-cytosamine (6), 2,3,6-trideoxyglucopyranosyl cytosine. Compound 1 inhibited the growth of Mycobacterium smegmatis (MIC = 32 µg/mL), while compounds 2-5 were not active at 50 µg/disc. Bamicetin (8) and amicetin (9) showed the MICs of 16 and 8 µg/mL, respectively.

Biofilm formation plays a critical role in antimicrobial resistance in Staphylococcus aureus. Here, we investigated the potential of crude extracts of 79 Micronesian marine microorganisms to inhibit S. aureus biofilm formation. An extract of Streptomyces sp. MC025 inhibited S. aureus biofilm formation. Bioactivity-guided isolation led to the isolation of a series of 2,2'-bipyridines: collismycin B (1), collismycin C (2), SF2738 D (3), SF2738 F (4), pyrisulfoxin A (5), and pyrisulfoxin B (6). Among these bipyridines, collismycin C (2) was found to be the most effective inhibitor of biofilm formation by methicillin-sensitive S. aureus and methicillin-resistant S. aureus (MRSA), and this compound inhibited MRSA biofilm formation by more than 90% at a concentration of 50 μg/mL. The antibiofilm activity of collismycin C was speculated to be related to iron acquisition and the presence and position of the hydroxyl group of 2,2'-bipyridines.

Linear nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) template the modular biosynthesis of numerous nonribosomal peptides, polyketides and their hybrids through assembly line chemistry. This chemistry can be complex and highly varied, and thus challenges our understanding in NRPS and PKS-programmed, diverse biosynthetic processes using amino acid and carboxylate building blocks. Here, we report that caerulomycin and collismycin peptide-polyketide hybrid antibiotics share an assembly line that involves unusual NRPS activity to engage a trans-acting flavoprotein in C-C bond formation and heterocyclization during 2,2'-bipyridine formation. Simultaneously, this assembly line provides dethiolated and thiolated 2,2'-bipyridine intermediates through differential treatment of the sulfhydryl group arising from L-cysteine incorporation. Subsequent L-leucine extension, which does not contribute any atoms to either caerulomycins or collismycins, plays a key role in sulfur fate determination by selectively advancing one of the two 2,2'-bipyridine intermediates down a path to the final products with or without sulfur decoration. These findings further the appreciation of assembly line chemistry and will facilitate the development of related molecules using synthetic biology approaches.