Enhancement of clavulanic acid production by mutant Streptomyces clavuligerus

β-lactam antibiotics are among the most popular classes of antibacterial agents, whose mechanism of action consists on the inhibition of bacterial cell wall synthesis.1 The production of β-lactamase is the most important mechanism for bacterial resistance to β-lactam antibiotics.2 Secondary metabolites produced by bacteria exhibit potent biological activities and have been developed extensively for antimicrobial, anticancer, and other vital therapeutic applications.3 In this sense, the CA is a secondary metabolite that was first detected in Streptomyces clavuligerus (S. clavuligerus) and is a potent inhibitor of a wide range of β-lactamases from pathogenic organisms. CA effectively inhibits the activity of β-lactamases of molecular classes A and D, such as cephalosporinases, penicillinases, and broad spectrum β-lactamases, and thus it has been widely used clinically to treat diseases caused by β-lactam resistant bacteria.4 The combined therapy of CA +β-lactam antibiotic has been very successful in preventing infections due to Gram-positive (Staphylococcus sp.) and Gram-negative (Klebsiella sp. Hemophilus sp. Proteus, Shigella, Pseudomonas) β-lactamase producing pathogens.1