Van Goethem, O. | Search bioRxiv

bioRxiv2025

Charting the biosynthetic landscape of hybrid polyketide-nonribosomal peptide-specialized lipids

Polyunsaturated fatty acid (PUFA) synthase-like enzymes are best known for their role in membrane lipid biosynthesis in marine bacteria, but have also been repurposed for the assembly of specialized lipid metabolites with unique biological functions. Here, we illuminate their broader biosynthetic potential by charting the unexplored landscape of hybrid peptide-polyketide-specialized lipid biosynthesis in bacteria. Using a targeted genome mining strategy, we identified more than 60 biosynthetic gene clusters that combine PUFA synthase-like, polyketide synthase (PKS), and nonribosomal peptide synthetase (NRPS) enzymes across diverse bacterial lineages. Comparative analysis revealed extensive diversification of these triple hybrid pathways through gene fusion, domain reshuffling and recruitment of accessory enzymes. We further expand the known repertoire of peptide-polyketide-specialized lipid hybrids by identifying the chitinimines, a new family of amphiphilic metabolites produced by Chitinimonas koreensis featuring a C22 polyunsaturated lipid chain conjugated to a cyclic peptide-polyketide and a pyruvate-derived cyclic acetal moiety. The chitinimines exhibit surfactant properties, as well as moderate antibacterial activity against Gram-positive bacteria and contribute to a growth-promoting interaction between C. koreensis and Salmonella spp. Together, these findings demonstrate that PUFA synthase-like systems are far more versatile than previously appreciated, playing a key role in combinatorial biosynthetic innovation and serving as a rich, untapped source of chemically and functionally diverse specialized lipids.

microbiology↗

bioRxiv2025

The ATO gene family governs Candida albicans colonisation in the dysbiotic gastrointestinal tract

The fungal pathogen Candida albicans colonises the human gut where short-chain fatty acids (SCFAs) offer sources of carbon. This fungus harbours one of the largest microbial families of ATO (Acetate Transport Ortholog) genes, which encode putative SCFA transport proteins. Here, we generate C. albicans null mutants lacking individual or all known putative SCFA transporter genes and compare their phenotypes in vitro and in vivo. We show that blocking ATO function in C. albicans impairs SCFA uptake and growth, particularly on acetate. The uptake of acetate is largely dependent on a functional Ato1 (also known as Frp3/Ato3) and it is effectively abolished upon deletion of all ATO genes. We further demonstrate that deletion of the entire ATO gene family, but not inactivation of ATO1 alone, compromises the stable colonisation of C. albicans in the murine gastrointestinal tract following bacterial disruption by broad-spectrum antibiotics. Our data suggest that the ATO gene family has expanded and diversified during the evolution of C. albicans to promote the fitness of this fungal commensal during gut colonisation, in part through SCFA utilisation. IMPORTANCEThe human gut is rich in microbial fermentation products such as SCFAs, which serve as key nutrients for both bacteria and fungi. C. albicans, a common fungal resident of the gut and a cause of opportunistic infections, carries an unusually large family of ATO genes. This study reveals that this ATO gene family is required for the efficient uptake of acetate, the most abundant SCFA in the gut, and for stable colonisation of the gut. These findings uncover a new layer of metabolic adaptation in fungal commensals of humans and suggest that transporter gene expansion can shape microbial fitness in response to environmental nutrient signals.

microbiology↗