The β-lactam antibiotics—penicillins, cephalosporins, carbapenems, and monobactams—share a common structure (β-lactam ring) and mechanism of action (i.e., inhibition of the synthesis of the bacterial peptidoglycan cell wall). Bacterial resistance against the β-lactam antibiotics continues to increase at a dramatic rate. β-Lactamase inhibitors such as clavulanate and avibactam can extend the utility of these antibiotics against β-lactamase–producing organisms. Unfortunately, resistance includes not only production of β-lactamases but also alterations in the bacterial enzymes targeted by β-lactam antibiotics, as well as decreased entry or active efflux of the antibiotic.
ADME: absorption, distribution, metabolism, excretion
CNS: central nervous system
CSF: cerebrospinal fluid
ESBL: extended-spectrum β-lactamase
KPC: Klebsiella pneumoniae carbapenemase
MDM: major determinant moiety
MRSA: methicillin-resistant Staphylococcus aureus
MRSE: methicillin-resistant Staphylococcus epidermidis
MSSA: methicillin-susceptible Staphylococcus aureus
PBP: penicillin-binding protein
PO: by mouth
MECHANISM OF ACTION: INHIBITION OF PEPTIDOGLYCAN SYNTHESIS
Peptidoglycan is a heteropolymeric component of the bacterial cell wall that provides rigid mechanical stability. The β-lactam antibiotics inhibit the last step in peptidoglycan synthesis (Figure 57–1).
Action of β-lactam antibiotics in Staphylococcus aureus. The bacterial cell wall consists of glycopeptide polymers (an NAM-NAG amino-hexose backbone) linked via bridges between amino acid side chains. In S. aureus, the bridge is (Gly)5-D-Ala between lysines. The cross-linking is catalyzed by a transpeptidase, the enzyme that penicillins and cephalosporins inhibit.
In gram-positive microorganisms, the cell wall is 50–100 molecules thick; in gram-negative bacteria, it is only 1 or 2 molecules thick (Figure 57–2A). The peptidoglycan is composed of glycan chains, which are linear strands of two alternating amino sugars (N-acetylglucosamine and N-acetylmuramic acid) that are cross-linked by peptide chains. Peptidoglycan precursor formation takes place in the cytoplasm. The synthesis of UDP–acetylmuramyl-pentapeptide is completed with the addition of a dipeptide, D-alanyl-D-alanine (formed by racemization and condensation of L-alanine). UDP-acetylmuramyl-pentapeptide and UDP-acetylglucosamine are linked (with the release of the uridine nucleotides) to form a long polymer. The cross-link is completed by a transpeptidation reaction that occurs outside the cell membrane (Figure 57–2B).
A. Structure and composition of gram-positive and gram-negative cell walls. B. PBP activity and inhibition. PBPs have two enzymatic activities that are crucial to synthesis of the peptidoglycan layers of bacterial cell walls: a TP that cross-links amino acid side chains and a GT that links subunits of the glycopeptide polymer (see Figure 57–1). The TP and GT domains are separated by a linker region. The glycosyltransferase is thought to be partially embedded in the membrane. (Part A reprinted with permission from Tortora G, et al. Microbiology: An Introduction, 3rd ed. Pearson, London, 1989...