Antibiotic production by Streptomyces clavuligerus

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Antibiotics produced by microbes are a main defense against infectious diseases, but their effectiveness is being threatened. Pathogenic bacteria are developing resistance to many of our most useful drugs at an alarming rate. Clavulanic acid is a beta-lactamase inhibitor that is widely used together with penicillin and cephalosporin antibiotics to overcome resistance mediated by production of beta-lactamases. All clavulanic acid used clinically comes from fermentations of the organism, Streptomyces clavuligerus. Production of clavulanic acid is being studied to understand how the appearance and disappearance of the biosynthetic enzymes involved in its synthesis is regulated in S. clavuligerus. The genes encoding these biosynthetic enzymes are spread across three gene clusters in the chromosome, and each gene cluster is regulated differently. We use mutagenesis and analysis of the resulting mutants to investigate the details of the biosynthesis of clavulanic acid biosynthesis. Studies on regulatory genes clarify the conditions under which the various biosynthetic enzymes will be produced. These studies could lead to more efficient production of existing antibiotics or possibly to the development of new types of antibiotics.