18: Exploring acyl-homoserine lactone analogs as quorum signal synthesis inhibitors in Bradyrhizobium Japonicum

Abstract: Quorum sensing is a population-counting, cell-to-cell communication mechanism that involves the production, detection, and response to chemical molecules termed "autoinducers." The acyl-homoserine lactone (AHL) autoinducers in Gram-negative bacteria are produced by a family of enzymes known as the AHL synthases. Across Gram-negative bacteria species, the AHL synthase recognizes two substrates known as S-adenosyl methionine and the acyl-ACP/acyl-CoA. Binding of these two substrates at the enzyme active site causes the production of holo-ACP, 5'-methylthioadenosine, and acyl-homoserine lactone as products. The development of small molecules that could compete at the AHL synthase enzyme active site could be a useful chemical tool to prevent the production of AHL molecules, ultimately preventing quorum sensing in bacteria. This study explores AHL derivatives as product analog inhibitors for AHL synthases. Our previous inhibition studies on the short-chain butyryl-ACP-preferring RhlI synthase from Pseudomonas aeruginosa revealed that long-chain, D-thiolactone analogs inhibited while their 3-oxoacyl counterparts activated the enzyme. We have expanded the chemical space of our AHL library to include additional modifications in the linker and the acyl chain. We are evaluating AHL analog specificity for a short-chain isovaleryl-CoA-preferring Bradyrhizobium japonicum BjaI AHL synthase. This study highlights differences in AHL analog specificities between short-chain acyl-ACP vs acyl-CoA-preferring AHL synthases, which will inform the development of AHL-based inhibitors for quorum signal synthases.