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

Fleurdeliz Maglangit* (Corresponding Author), Yuting Zhang, Kwaku Kyeremeh, Hai Deng* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticle

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 B112 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.
Original languageEnglish
Article number1464
Number of pages11
JournalBiomolecules
Volume10
Issue number10
DOIs
Publication statusPublished - 20 Oct 2020

Keywords

  • accramycin
  • type II polyketides
  • Streptomyces sp. MA37
  • regulatory genes
  • gene inactivation
  • titer improvement
  • antibacterial activities
  • multidrug resistant Enterococcus

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