β-Lactamases: Why and How

Abstract

The targets of β-lactam antibiotics are bacterial DD-peptidases that catalyze the final steps of peptidoglycan biosynthesis. Bacterial resistance to β-lactams is achieved by the production of β-lactamases, enzymes that catalyze β-lactam hydrolysis. Structural studies of both of these groups of enzymes, their substrates and of β-lactams have led to the conclusion that β-lactamases have evolved from a DD-peptidase ancestor. Thus, the active sites of DD-peptidases and serine β-lactamases are very similar. Why is it then that the active site of a serine β-lactamase can catalyze hydrolysis of a β-lactam while that of a DD-peptidase cannot? In view of the active site similarities, why was it necessary for β-lactamases to evolve at all? The aim of this review is to examine our current understanding of these issues in terms of the crystal structures of the relevant enzymes that are now available, rounding off the analysis with speculation where necessary.

Lytic transglycosylases: concinnity in concision of the bacterial cell wall

“…β-Lactam antibiotics obstruct cell-wall synthesis by covalent inactivation of these enzymes. The β-lactam ring (of the penicillin, cephalosporin, and carbapenem antibiotics) mimics the D-Ala-D-Ala segment of the muropeptide stem of the peptidoglycan (Lee et al , 2001; Lee et al , 2003; Pratt, 2016). PBPs act on this same muropeptide stem as their substrate.…”

A system-level mechanistic investigation of traditional Chinese medicine, Yinlai Decoction, for related diseases

“…YD is effective in amiolerating lung condition, relieving exterior syndrome, relaxing the bowels and removing food retention, and has been used for treating pediatric diseases, especially pneumonia and recurrent respiratory tract infection [9][10][11][12][13][14].…”

Constructing and deconstructing the bacterial cell wall

“…In the second half‐reaction this acyl moiety is transferred to the primary amine of the amino acid found at the third position—an l ‐Lys or an l ‐Lys modified in its side chain by Gly residues—on the stem of an adjacent glycan strand, thus crosslinking the two. β‐Lactams are structural mimics of the acyl‐ d ‐Ala‐ d ‐Ala terminus of the stem peptide . PBPs are inactivated when β‐lactams are bound as acyl‐ d ‐Ala‐ d ‐Ala mimetics at the active site, and complete the first half‐reaction to form an acyl‐enzyme, but are incompetent for acyl‐transfer and thus are inactivated (Figure ).…”

“…β-Lactams are structural mimics of the acyl-D-Ala-D-Ala terminus of the stem peptide. [138][139][140] PBPs are inactivated when β-lactams are bound as acyl-D-Ala-D-Ala mimetics at the active site, and complete the first half-reaction to form an acylenzyme, but are incompetent for acyl-transfer and thus are inactivated ( Figure 1). In contrast to PBP2, PBP2a is a monofunctional enzyme.…”