Discovery of new antibacterial accramycins from a genetic variant of the soil bacterium,Streptomycessp. MA37

Abstract Continued mining of natural products from the strain Streptomyces sp. MA37 in our laboratory led to the discovery of a minor specialised metabolite (SM) called accramycin A. Owing to its low yield (0.2mg/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 titre of this compound. One of the resulting mutants (Δ accJ ) dramatically upregulated the production of accramycin A 1 by 330-fold (66mg/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 ( S. aureus, E. faecalis ) and clinical isolates, E. faecium (K59-68 and K60-39), and S. haemolyticus with minimal inhibitory concentration (MIC) values in the range of 1.5-12.5µg/mL. Remarkably, compounds 1-13 displayed superior activity against K60-39 (MIC = 3.1-6.3µg/mL) than ampicillin (MIC = 25µg/mL), and offer 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.