Research into new antibiotics is becoming increasingly important as antibiotic resistance increases worldwide. The genus Streptomyces in particular is able to produce a wide range of antimicrobial products due to the large number of biosynthetic gene clusters (BGCs) in its genome. However, not all BGCs are expressed under laboratory conditions. In this work, deletion of the gene wblA, encoding a global regulator of natural product biosynthesis and morphogenesis in Streptomyces, led to the production of a novel natural product, olikomycin A, in Streptomyces ghanaensis ATCC 14672. Complete structure elucidation revealed that olikomycin A belongs to a class of calcium-dependent antibiotics known as non-ribosomal peptide synthetase (NRPS)-encoded acidic lipopeptides. These compounds exhibit remarkable antimicrobial activity in the presence of calcium. Insights into olikomycin A biosynthesis were provided by whole genome sequencing and gene inactivation studies, while bioactivity assays showed strong inhibition of the growth of multidrug-resistant Gram-positive pathogens via disrupting cell membrane integrity. Olikomycin A shows an antibiotic profile similar to that of daptomycin, which is already in clinical use.
Keywords: Antibiotics; BGC activation; Genetic manipulation; NRPS; Peptides; Streptomyces.
© 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH.