Abstract
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 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 (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.
Highlights
Naphthacemycins and congeners are a class of rare aromatic polyketides consisting of a partially reduced 1-phenyltetracene pentacyclic core [1,2,3]
Only the extract from the ∆accJ variant displayed a significant metabolic profile in high pressure liquid chromatography (HPLC) and high-resolution electrospray ionization mass spectrometry (HRESIMS) analyses compared with the wild type (WT) (Figure S2)
We confirmed that accJ is a repressor gene in accramycin biosynthesis
Summary
Naphthacemycins and congeners are a class of rare aromatic polyketides consisting of a partially reduced 1-phenyltetracene pentacyclic core [1,2,3] This group of specialized metabolites (SM) display potent activity against various multidrug-resistant Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE) [4]. This can be exemplified by the recently discovered naphthacemycin congeners, fasamycins [4,5,6], formicamycins [4], and streptovertimycins [7] (Figure 1). Two mono-chlorinated accramycin derivatives were tentatively assigned via molecular network analysis Both derivatives, could not be isolated due to their minute quantities in the extract [25]
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