Abstract
Peptidoglycan (PG) is an essential macromolecular sacculus surrounding most bacteria. It is assembled by the glycosyltransferase (GT) and transpeptidase (TP) activities of multimodular penicillin-binding proteins (PBPs) within multiprotein complex machineries. Both activities are essential for the synthesis of a functional stress-bearing PG shell. Although good progress has been made in terms of the functional and structural understanding of GT, finding a clinically useful antibiotic against them has been challenging until now. In contrast, the TP/PBP module has been successfully targeted by β-lactam derivatives, but the extensive use of these antibiotics has selected resistant bacterial strains that employ a wide variety of mechanisms to escape the lethal action of these antibiotics. In addition to traditional β-lactams, other classes of molecules (non-β-lactams) that inhibit PBPs are now emerging, opening new perspectives for tackling the resistance problem while taking advantage of these valuable targets, for which a wealth of structural and functional knowledge has been accumulated. The overall evidence shows that PBPs are part of multiprotein machineries whose activities are modulated by cofactors. Perturbation of these systems could lead to lethal effects. Developing screening strategies to take advantage of these mechanisms could lead to new inhibitors of PG assembly. In this paper, we present a general background on the GTs and TPs/PBPs, a survey of recent issues of bacterial resistance and a review of recent works describing new inhibitors of these enzymes.
Highlights
Peptidoglycan (PG) is an essential macromolecular sacculus surrounding most bacteria
Nascent glycan strands are first polymerized by the glycosyltransferases (GTs) using the lipid II precursor (undecaprenyl-pyrophosphoryl-MurNAc-(pentapeptide)-GlcNAc) as a substrate [2,3], and cross-linked between them and with the pre-existing cell wall by the penicillin-binding proteins (PBPs)/transpeptidases (TPs) (Figure 1) [4,5]
The GT51 is considered a validated target based on the essentiality of the class A PBPs in peptidoglycan synthesis in most bacteria (E. coli, S. aureus, S. pneumoniae, etc. . . . ) and the antibacterial activity of moenomycin which binds to the active site of the GT
Summary
Peptidoglycan (PG) is an essential macromolecular sacculus surrounding most bacteria. PG determines the bacterium cell shape and provides protection from rupture under the high cytoplasmic osmotic pressure [1]. The PG structure consists of glycan strands made of alternating β-1,4-linked. N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) residues cross-linked by peptides [1]. Nascent glycan strands are first polymerized by the glycosyltransferases (GTs) using the lipid II precursor (undecaprenyl-pyrophosphoryl-MurNAc-(pentapeptide)-GlcNAc) as a substrate [2,3], and cross-linked between them and with the pre-existing cell wall by the penicillin-binding proteins (PBPs)/transpeptidases (TPs) (Figure 1) [4,5]. The activities and regulation of GTs and TPs are coupled to provide a concerted knitting and enlargement of the PG sacculus [6,7,8,9,10].
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