Glycosyltransferases and Transpeptidases/Penicillin-Binding Proteins: Valuable Targets for New Antibacterials

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.

Keywords: antibiotics resistance; glycosyltransferase; lipid II; penicillin-binding proteins; peptidoglycan; transpeptidase; β-lactam.

Figure 1

Schematic representation of the glycosyltransferase and transpeptidase reactions catalyzed by penicillin-binding proteins.

Figure 2

Structure of E. coli class A PBP1b [34], class B PBP3 [32], class C PBP4 [35], and class C PBP5 [36]. The TP domains are shown with brown helices and orange strands, the red sphere indicating the position of the active site serine. The PBP1b GT domain is shown with helices colored in lime green and strands in brick color. The GT catalytic centre (Glu233) is shown with a pink sphere.

Figure 3

Structures of transpeptidase inhibitors.

Figure 4

Superimposition of two structures of S. aureus MtgA, PDB 3VMR (yellow) and PDB 3HZS (red). Moenomycin (green) bound to the donor site and a lipid II analog (cyan) bound to the acceptor site are represented in stick. The mobile region between the two sites is highlighted by a circle.

Figure 5

Structures of the lipid II substrate and the glycosyltransferase inhibitor moenomycin A and their recent synthetic analogs shown to inhibit GT activity. The compounds are numbered as in the original papers and the references are indicated in square brackets.

Figure 6

Structures of small molecule inhibitors of glycosyltrasferases. The compounds are numbered as in the original papers and the references are indicated in square brackets.