Penicillin

Penicillin is a \(\beta \) -lactam antibiotic discovered by Alexander Fleming. Today, a range of natural and synthetic \(\beta \) -lactam drugs have entered the clinic. Penicillin’s mechanism of action involves the inhibition of cell wall synthesis by binding to transpeptidase: the enzyme that forms tetrapeptide linkages in the peptidoglycan component of the cell wall. The mechanism of action of penicillin can be deciphered from simple experiments with protoplasts lacking a cell wall. Delving deeper, penicillin’s observed substrate analogy with (D-ala)-(D-ala) leads to the discovery of transpeptidases. Penicillin binding to transpeptidase can be confirmed by a range of experiments, including affinity chromatography, the SYPRO Orange thermal shift assay, and X-ray crystallography. Bacteria evolve resistance to penicillin via mutations to transpeptidase, the evolution of \(\beta \) -lactamases, and the use of multidrug efflux pumps.