Synergistic activity of cosecreted natural products from amoebae-associated bacteria

Abstract

<p id="d4595468e344">Bacterially produced small molecules are indispensable leads in the development of antibiotics, anticancer therapeutics, or immunomodulators. To unveil novel aspects in the biosynthetic potential of bacteria, a consideration of the ecological context in which the adapted producers thrive is extremely insightful. Here, we describe two natural products produced by <i>Pseudomonas</i> sp. QS1027, a bacterium that resides in the vicinity of the bacterial predator <i>Dictyostelium discoideum</i>. The two metabolites are jessenipeptin, a nonribosomal cyclic lipopeptide, and mupirocin, a known polyketide antibiotic. Both compounds are quorum-sensing regulated and display potent synergistic inhibitory activity against clinically relevant methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). </p><p class="first" id="d4595468e356">Investigating microbial interactions from an ecological perspective is a particularly fruitful approach to unveil both new chemistry and bioactivity. Microbial predator–prey interactions in particular rely on natural products as signal or defense molecules. In this context, we identified a grazing-resistant <i>Pseudomonas</i> strain, isolated from the bacterivorous amoeba <i>Dictyostelium discoideum.</i> Genome analysis of this bacterium revealed the presence of two biosynthetic gene clusters that were found adjacent to each other on a contiguous stretch of the bacterial genome. Although one cluster codes for the polyketide synthase producing the known antibiotic mupirocin, the other cluster encodes a nonribosomal peptide synthetase leading to the unreported cyclic lipopeptide jessenipeptin. We describe its complete structure elucidation, as well as its synergistic activity against methicillin-resistant <i>Staphylococcus aureus</i>, when in combination with mupirocin. Both biosynthetic gene clusters are regulated by quorum-sensing systems, with 3-oxo-decanoyl homoserine lactone (3-oxo-C10-AHL) and hexanoyl homoserine lactone (C6-AHL) being the respective signal molecules. This study highlights the regulation, richness, and complex interplay of bacterial natural products that emerge in the context of microbial competition. </p>