The detection of a protein then called lysozyme in 1921 by Alexander Fleming marked the beginning of the discovery of penicillin in 1928 and led to its mass production for therapeutic use in the 1940s. (1) Shortly after the introduction of penicillin, resistant strains of staphylococci began to appear and within five years, the bulk of Staphylococcus aureus hospital isolates were resistant to penicillin G. (1)
Beta-lactams are a broad group of widely prescribed antibiotics characterized by a common structure, the beta-lactam ring. (2, 3) Examples of beta-lactam antibiotics include penicillins, cephalosporins, carbapenems, monobactams, and cephamycins. (4) Beta-lactams are broadly used to treat an infections caused by gram positive and gram-negative organisms.
Bacteria depend on the integrity of their unique cell wall to maintain the cell’s shape and rigidity. The target of beta-lactam antibiotics is the penicillin-binding proteins (PBPs), enzymes vital for bacterial cell wall synthesis as they catalyze the last steps of peptidoglycan synthesis. (2,3, 5-7)
Peptidoglycan synthesis starts inside the cells with the production of the N-acetylmuramic acid (NAM)-pentapeptide. This structure is then attached to a “conveyor belt” in the cytoplasmic membrane. N-acetylglucosamine (NAG) is added to form the building block of the peptidoglycan (NAG-NAM-pentapeptide). This building block is then translocated to the outside of the cell where it is cross-linked to the existent peptidoglycan structure by peptide bond exchange (transpeptidation) carried out by PBPs. PBPs also have carboxypeptidase functions, removing the terminal D-Ala which limit the extent of cross-linking. (3, 5-7)
As the beta-lactam ring is sterically similar to the D-alanine-D-alanine of the peptide attached to NAM the PBPs mistakenly use the beta-lactam ring in the cell wall synthesis, acylation of the PBP follows making the enzyme unable to hydrolyze the peptide D-Ala, hindering further cell wall synthesis; cell wall degradation continues, leading to the final lysis of the bacterial cell. (5-7)
Bacteria have developed forms of resistance to beta lactams. (1-4) Four main resistance mechanisms for beta-lactams have been identified: decrease permeability, efflux, alteration of the target site, and enzymatic degradation of the beta-lactam ring. (6,8)