Genomic Diversity of Streptomyces clavuligerus: Implications for Clavulanic Acid Biosynthesis and Industrial Hyperproduction

Abstract

Streptomyces clavuligerus is a species used worldwide to industrially produce clavulanic acid (CA), a molecule that enhances antibiotic effectiveness against β-lactamase-producing bacterial strains. Despite its low inherent CA production, hyper-producing strains have been developed. However, genomic analyses specific to S. clavuligerus and CA biosynthesis are limited. Genomic variations that may influence CA yield were explored using S. clavuligerus strain genomes from diverse sources. Despite the slight differences obtained by similarity index calculation, pan-genome estimation revealed that only half of the genes identified were present in all strains. As expected, core genes were associated with primary metabolism, while the remaining genes were linked to secondary metabolism. Differences at the sequence level were more likely to be found in regions close to the tips of the linear chromosome. Wild-type strains preserved larger chromosomal and plasmid regions compared to industrial and/or hyper-producing strains; such a grouping pattern was also found through refined phylogenetic analyses. These results provide essential insights for the development of hyper-producing S. clavuligerus strains, attending to the critical demand for this antibiotic enhancer and contributing to future strategies for CA production optimization.