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Continued mining of natural products from the strain Streptomyces sp. MA37 in our laboratory led to the discovery of a minor specialized metabolite (SM) called accramycin A. Owing to its low yield (0.2 mg/L) in the wild type strain, we investigated the roles of regulatory genes in the corresponding biosynthetic gene cluster ( acc BGC) through gene inactivation with the aim of improving the titer of this compound. One of the resulting mutants (∆ accJ ) dramatically upregulated the production of accramycin A 1 by 330-fold (66 mg/L). Furthermore, ten new metabolites, accramycins B-K 2 - 11 , were discovered, together with two known compounds, naphthacemycin B 1  12 and fasamycin C 13 from the mutant extract. This suggested that accJ , annotated as multiple antibiotic resistance regulator (MarR), is a negative regulator gene in the accramycin biosynthesis. Compounds 1 - 13 inhibited the Gram-positive pathogens ( Staphylococcus aureus, Enterococcus faecalis ) and clinical isolates Enterococcus faecium (K59-68 and K60-39) and Staphylococcus haemolyticus with minimal inhibitory concentration (MIC) values in the range of 1.5-12.5 µg/mL. Remarkably, compounds 1 - 13 displayed superior activity against K60-39 (MIC = 3.1-6.3 µg/mL) compared to ampicillin (MIC = 25 µg/mL), and offered promising potential for the development of accramycin-based antibiotics that target multidrug-resistant Enterococcus clinical isolates. Our results highlight the importance of identifying the roles of regulatory genes in natural product discovery.

Discovery of New Antibacterial Accramycins from a Genetic Variant of the Soil Bacterium, Streptomyces sp. MA37