Copper inhibits peptidoglycan LD-transpeptidases suppressing β-lactam resistance due to bypass of penicillin-binding proteins

Significance The antimicrobial effect of copper has been known since ancient times and it is well known that copper alloy surfaces kill various disease-causing bacteria, fungi, and viruses, preventing the spread of antibiotic resistance through horizontal gene transfer between pathogens. However, there is little knowledge about specific targets of copper toxicity in bacteria. Here we show that copper inhibits peptidoglycan LD-transpeptidases, causing higher permeability in the outermembrane and precluding strains of Escherichia coli and Enterococcus faecium to utilize these enzymes in a bypass mechanism to achieve β-lactam resistance. Hence, copper affects bacterial cell envelope biogenesis at low concentration that does not affect growth rate.