β-Lactam Antibiotics: Mechanisms of Resistance

MECHANISMS OF RESISTANCE

A number of microorganisms have evolved mecha-nisms 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 hy-drolysis of the β-lactam ring by β-lactamases (penicilli-nases and cephalosporinases). Many bacteria (Staphylo-coccus 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 mole-cule, then deacylate and hydrolyze the β-lactam ring. Some bacteria have chromosomal (inducible) genes for β-lactamases. Other bacteria acquire β-lactamase genes via plasmids or transposons. Transfer of β-lactamase genes between bacterial species has contributed to the proliferation of resistant organisms resulting in the ap-pearance of clinically important adverse consequences.

Efforts to overcome the actions of the β-lactamases have led to the development of such β-lactamase in-hibitors as clavulanic acid, sulbactam, and tazobactam. They are called suicide inhibitors because they perma-nently bind when they inactivate β-lactamases. Among the β-lactamase inhibitors, only clavulanic acid is avail-able 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 re-sistant to clavulanic acid include the cephalosporinases produced by Citrobacter spp., Enterobacter spp., and Pseudomonas aeruginosa.

An additional mechanism of antibiotic resistance in-volves an alteration of PBPs. Resistant bacteria, usually gram-positive organisms, produce PBPs with low affin-ity for β-lactam antibiotics. The development of muta-tions of bacterial PBPs is involved in the mechanism for β-lactam resistance in Streptococcus pneumoniae, Enterococcus faecium, and methicillin-resistant S. au-reus (MRSA).

Some gram-negative bacteria employ a third mech-anism of resistance, namely, one that reduces antibiotic access to PBPs. Gram-positive organisms have an ex-posed peptidoglycan layer easily accessible to β-lactam antibiotics (Fig. 45.2). In contrast, gram-negative organ-isms have an outer membrane surrounding the peptido-glycan layer. 

The gram-negative outer membrane hin-ders ingress of large molecules and helps bacteria resist the actions of antibiotics. In susceptible gram-negative bacteria, protein channels (porins) allow β-lactam an-tibiotics to traverse the outer membrane and interact with PBPs in the periplasmic space. In resistant bacteria like P. aeruginosa, porin mutants impede the β-lactam transfer across the outer membrane.

Finally, some gram-negative organisms demonstrate a fourth mechanism of resistance. For example, strains of P. aeruginosa produce xenobiotic efflux pumps to eject antibiotics. Drug efflux mechanisms are associated with multiple drug resistance, including resistance to β-lactam antibiotics.

Widespread use of β-lactam antibiotics exerts selec-tive pressure on bacteria and permits the proliferation of resistant organisms. A comparison of current antibi-ograms with those from previous decades shows an alarming increase in bacterial resistance to β-lactam an-tibiotics.