Practice question

Resistance to beta-lactam antibiotics including penicillins, cephalosporins, monobactams and carbapenems frequently arises through enzymatic destruction rather than target alteration. Beta-lactamases are hydrolases classified into Ambler molecular classes A to D based on amino acid sequence homology and catalytic mechanism. Serine beta-lactamases, including plasmid-encoded TEM-1, SHV-1, extended-spectrum beta-lactamases CTX-M and serine carbapenemases KPC, employ an active-site serine residue that performs nucleophilic attack on carbonyl carbon of the strained beta-lactam ring, forming a transient covalent acyl-enzyme intermediate that is rapidly hydrolyzed by activated water molecule, opening the ring irreversibly and rendering drug unable to acylate PBPs. Metallo-beta-lactamases like NDM, VIM and IMP are class B enzymes that use one or two Zn2+ ions to polarize water for direct nucleophilic attack, capable of hydrolyzing almost all beta-lactams except aztreonam. Production can be chromosomally encoded or plasmid-encoded, inducible or constitutive, often associated with porin loss compounding resistance. DNA gyrase is target of fluoroquinolones, catalase detoxifies hydrogen peroxide, transpeptidase is the drug target rather than resistance enzyme, distinguishing beta-lactamase as the specific deactivating enzyme responsible for clinical failure of beta-lactams.