Solanimycin: Biosynthesis and Distribution of a New Antifungal Antibiotic Regulated by Two Quorum-Sensing Systems

• Published in: mBio Vol. 13; no. 6; p. e0247222
• Main Authors: Matilla, Miguel A, Monson, Rita E, Murphy, Annabel, Schicketanz, Muriel, Rawlinson, Alison, Duncan, Caia, Mata, Juan, Leeper, Finian, Salmond, George P C
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 20.12.2022
• Subjects: acyl-homoserine lactone; agriculture and global food security; Animals; Anti-Bacterial Agents - metabolism; antibiotics; antifungal agents; Antifungal Agents - metabolism; Bacteria - metabolism; Dickeya solani; Enterobacteriaceae - genetics; Fungi - metabolism; gene regulation; Humans; Phylogeny; Plant Microbiology; Research Article; acyl-homoserine lactone; antifungal agents; quorum sensing; Dickeya solani; agriculture and global food security; hybrid polyketide/nonribosomal peptide; post-transcriptional control mechanisms; gene regulation; secondary metabolism; phytopathogens; antibiotics; horizontal gene transfer
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mbio.02472-22

The increasing emergence of drug-resistant fungal infections has necessitated a search for new compounds capable of combating fungal pathogens of plants, animals, and humans. Microorganisms represent the main source of antibiotics with applicability in agriculture and in the clinic, but many aspects of their metabolic potential remain to be explored. This report describes the discovery and characterization of a new antifungal compound, solanimycin, produced by a hybrid polyketide/nonribosomal peptide (PKS/NRPS) system in Dickeya solani, the enterobacterial pathogen of potato. Solanimycin was active against a broad range of plant-pathogenic fungi of global economic concern and the human pathogen Candida albicans. The genomic cluster responsible for solanimycin production was defined and analyzed to identify the corresponding biosynthetic proteins, which include four multimodular PKS/NRPS proteins and several tailoring enzymes. Antifungal production in D. solani was enhanced in response to experimental conditions found in infected potato tubers and high-density fungal cultures. Solanimycin biosynthesis was cell density dependent in D. solani and was controlled by both the ExpIR acyl-homoserine lactone and Vfm quorum-sensing systems of the bacterial phytopathogen. The expression of the solanimycin cluster was also regulated at the post-transcriptional level, with the regulator RsmA playing a major role. The solanimycin biosynthetic cluster was conserved across phylogenetically distant bacterial genera, and multiple pieces of evidence support that the corresponding gene clusters were acquired by horizontal gene transfer. Given its potent broad-range antifungal properties, this study suggests that solanimycin and related molecules may have potential utility for agricultural and clinical exploitation. Fungal infections represent a major clinical, agricultural, and food security threat worldwide, which is accentuated due to the difficult treatment of these infections. Microorganisms represent a prolific source of antibiotics, and current data support that this enormous biosynthetic potential has been scarcely explored. To improve the performance in the discovery of novel antimicrobials, there is a need to diversify the isolation niches for new antibiotic-producing microorganisms as well as to scrutinize novel phylogenetic positions. With the identification of the antifungal antibiotic solanimycin in a broad diversity of phytopathogenic spp., we provide further support for the potential of plant-associated bacteria for the biosynthesis of novel antimicrobials. The complex regulatory networks involved in solanimycin production reflect the high metabolic cost of bacterial secondary metabolism. This metabolic regulatory control makes many antibiotics cryptic under standard laboratory conditions, and mimicking environmental conditions, as shown here, is a strategy to activate cryptic antibiotic clusters.