The bacterial cellular envelope typically consists of the inner membrane, the cell wall, and, in gram-negative organisms, the outer membrane. The cell envelope is a key target for antibacterial agents, including the β-lactam antibiotics, glycopeptides, and lipopeptides, as well as other minor classes (including bacitracin, discussed below, and polymyxins, discussed in Chapter 59). 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). β-Lactams are the single most important antibacterial class given their broad and varied spectrum of activity, their potent antibacterial killing, and their generally favorable tolerability. Unfortunately, resistance to β-lactams has steadily increased, requiring development of new agents, which can evade (e.g., ceftaroline) or neutralize (e.g., β-lactamase inhibitors) these mechanisms. The glycopeptides, including vancomycin, and lipopeptides (daptomycin) provide important treatment alternatives for infections due to gram-positive organisms.
ESBL: extended-spectrum β-lactamase
KPC: Klebsiella pneumoniae carbapenemase
MIC: minimum inhibitory concentration
MRSA: methicillin-resistant Staphylococcus aureus
MRSE: methicillin-resistant Staphylococcus epidermidis
PBP: penicillin-binding protein
β-LACTAMS: MECHANISMS OF ACTION
The bacterial cell wall is comprised of heteropolymeric peptidoglycan that provides rigid mechanical stability. The β-lactam antibiotics inhibit the last step in peptidoglycan synthesis. In gram-positive microorganisms, the cell wall is 50 to 100 molecules thick; in gram-negative bacteria, it is only one or two molecules thick (Figure 58–1A). 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, which is 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 plasma membrane (Figure 58–1B).
A. Structure and composition of gram-positive and gram-negative cell envelope. B. Penicillin binding protein (PBP) activity and inhibition. PBPs have two enzymatic activities that are crucial to synthesis of the peptidoglycan layers of bacterial cell walls: a transpeptidase that cross-links amino acid side chains, as shown for gram-positives, and a glycosyltransferase that links subunits of the glycopeptide polymer. The transpeptidase and glycosyltransferase domains are separated by a linker region. The glycosyltransferase is thought to be partially embedded in the membrane.
The β-lactam antibiotics inhibit this last step in peptidoglycan synthesis (Figure 58–2) by acylating the transpeptidase via cleavage of the –CO–N– bond of the β-lactam ring. The transpeptidase targets for the actions of β-lactam antibiotics are collectively termed penicillin-binding proteins (PBPs). Notably, bacteria may produce multiple ...