Dr. Kapil Tahlan - December 7, 2020

Comparative genomics and metabolomics analyses of clavulanic acid-producing Streptomyces species provides insight into specialized metabolism and evolution of β-lactam biosynthetic gene clusters

Clavulanic acid is a bacterial specialized metabolite, which inhibits certain serine β-lactamases; enzymes that inactivate β-lactam antibiotics to confer resistance. Due to this activity, clavulanic acid is widely used in combination with penicillin and cephalosporin (β-lactam) antibiotics to treat infections caused by β-lactamase producing bacteria. Clavulanic acid is industrially produced by fermenting Streptomyces clavuligerus, as large-scale chemical synthesis is not commercially feasible. Other than S. clavuligerus, only two other species are known to produce the metabolite, but information regarding their genome sequences was not available. In addition, the Streptomyces contain many biosynthetic gene clusters thought to be “cryptic,” as the specialized metabolites produced by them are not known. Therefore, we sequenced the genomes of select species and examined their metabolomes using untargeted mass spectrometry. We also analyzed their biosynthetic capacities by matching gene clusters with the specialized metabolites detected. Based on our analyses, we propose the core set of genes responsible for clavulanic acid biosynthesis and discuss possible mechanisms involved in the evolution and dissemination of gene clusters involved in producing such medicinally important metabolites. In addition, we used the strategy to guide the production of metabolites previously not known to be synthesized by such organisms.