Discovery of new antibacterial accramycins from a genetic variant of the soil bacterium, Streptomyces sp. 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 ({Delta}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 B1 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 1.5-12.5{micro}g/mL. Remarkably, compounds 1-13 displayed superior activity against K60-39 (MIC = 3.1-6.3{micro}g/mL) than ampicillin (MIC = 25{micro}g/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.