β-LACTAM ANTIBIOTICS

A number of antibiotics produced by fungi of the genus Cephalosporium have been identified.These antibiotics called cephalosporins contain, in common with the penicillins, a β-lactam ring. In addition to the numerous penicillins and cephalosporins in use, three other classes of β-lactam antibiotics are available for clinical use. These are the carbapenems, the carbacephems, and the monobactams. All  β-lactam antibiotics have the same bactericidal mechanism of action. They block a critical step in bacterial cell wall synthesis

                                                                                               

MECHANISM OF ACTION

The final reaction in bacterial cell wall synthesis is a cross-linking of adjacent peptidoglycan (murein) strands by a transpeptidation reaction. In this reaction, bacterial transpeptidases cleave the terminal D-alanine from a pentapeptide on one peptidoglycan strand and then cross-link it with the pentapeptide of another peptidoglycan strand. The cross-linked peptidoglycan (murein) strands give structural integrity to cell walls and permit bacteria to survive environments that do not match the organism’s internal osmotic pressure.

The β-lactam antibiotics structurally resemble the terminal D-alanyl-D-alanine (D-Ala-D-Ala) in the pentapeptides on peptidoglycan (murein). Bacterial transpeptidases covalently bind the β--lactam antibiotics at the enzyme active site, and the resultant acyl enzyme molecule is stable and inactive. The intact β-lactam ring is required for antibiotic action. The β-lactam ring modifies the active serine site on transpeptidases and blocks further enzyme function.In addition to transpeptidases, other penicillin-binding proteins (PBPs) function as transglycosylases and carboxypeptidases. All of the PBPs are involved with assembly, maintenance, or regulation of peptidoglycan cell wall synthesis.When β-lactam antibiotics inactivate PBPs, the consequence to the bacterium is a structurally weakened cell wall, aberrant morphological form, cell lysis, and death.

MECHANISMS OF RESISTANCE

A number of microorganisms have evolved mechanisms to overcome the inhibitory actions of the β-lactam antibiotics. There are four major mechanisms of resistance: inactivation of the  β--lactam ring, alteration of PBPs, reduction of antibiotic access to PBPs, and elaboration of antibiotic efflux mechanisms. Bacterial resistance may arise from one or more than one of these mechanisms. The most important mechanism of resistance is hydrolysis of the  β--lactam ring by β--lactamases (penicillinases and cephalosporinases). Many bacteria (Staphylococcus aureus, Moraxella [Branhamella] catarrhalis, Neisseria gonorrhoeae, Enterobacteriaceae, Haemophilus influenzae, and Bacteroides spp.) possess β—lactamases that hydrolyze penicillins and cephalosporins. The β-lactamases evolved from PBPs and acquired the capacity to bind β--lactam antibiotics, form an acyl enzyme molecule, then deacylate and hydrolyze the  β--lactam ring. Some bacteria have chromosomal (inducible) genes for β--lactamases. Other bacteria acquire -lactamase genes via plasmids or transposons. Transfer of β—lactamase genes between bacterial species have contributed to the proliferation of resistant organisms resulting in the appearance of clinically important adverse consequences. Efforts to overcome the actions of the β-lactamases have led to the development of such β--lactamase inhibitors as clavulanic acid, sulbactam, and tazobactam. They are called suicide inhibitors because they permanently bind when they inactivate β--lactamases. Among the  β--lactamase inhibitors, only clavulanic acid is available for oral use. Chemical inhibition of β--lactamases, however, is not a permanent solution to antibiotic resistance, since some β--lactamases are resistant to clavulanic acid, tazobactam, or sulbactam. Enzymes resistant to clavulanic acid include the cephalosporinases produced by Citrobacter spp., Enterobacter spp and Pseudomonas aeruginosa.