Penicillin-binding proteins (PBP)-mediated resistance is the key mechanism of β-lactam resistance in both Gram-negative and Gram-positive pathogens.

This review describes the types of PBPs and the effect of mutations that lead to antibiotic binding specificity/affinity on β-lactam resistance in ESKAPE pathogens. Further, it highlights the importance of multiple PBP-binding antibiotics in the treatment of infectious diseases.

Few β-lactamase inhibitors could potentially bind to PBP2 and exhibit antimicrobial activity.