Staphylococcus aureus cell wall maintenance - the multifaceted roles of peptidoglycan hydrolases in bacterial growth, fitness, and virulence

Abstract

Staphylococcus aureus is an important human and livestock pathogen that is well-protected against environmental insults by a thick cell wall. Accordingly, the wall is a major target of present-day antimicrobial therapy. Unfortunately, S. aureus has mastered the art of antimicrobial resistance, as underscored by the global spread of methicillin-resistant S. aureus (MRSA). The major cell wall component is peptidoglycan. Importantly, the peptidoglycan network is not only vital for cell wall function, but it also represents a bacterial Achilles' heel. In particular, this network is continuously opened by no less than 18 different peptidoglycan hydrolases (PGHs) encoded by the S. aureus core genome, which facilitate bacterial growth and division. This focuses attention on the specific functions executed by these enzymes, their subcellular localization, their control at the transcriptional and post-transcriptional levels, their contributions to staphylococcal virulence and their overall importance in bacterial homeostasis. As highlighted in the present review, our understanding of the different aspects of PGH function in S. aureus has been substantially increased over recent years. This is important because it opens up new possibilities to exploit PGHs as innovative targets for next-generation antimicrobials, passive or active immunization strategies, or even to engineer them into effective antimicrobial agents.

Keywords: Staphylococcus aureus; antimicrobial susceptibility; cell wall; pathogenesis; peptidoglycan hydrolase; subcellular protein localization.

Figure 1.

Different stages in the cell cycle of Staphylococcus aureus as visualized by transmission electron microscopy. During the initial phase of the cell cycle (stage 1), a spherical S. aureus mother cell will become slightly enlarged and forms a septum at the mid-cell position (stage 2). Once the synthesis of the septum is complete and the cell is further enlarged (stage3), bacterial autolytic enzymes will promote cell division, resulting in two daughter cells (stage 1). After cell separation, the septum of the daughter cells is reshaped from a flat surface into a hemisphere. Images were recorded by transmission electron microscopy. The magnification is indicated by scale bars (1 μm).

Figure 2.

Schematic representation of the S. aureus cell envelope structure. The S. aureus cell envelope is composed of a cytoplasmic membrane that is surrounded by a thick layer of peptidoglycan. For peptidoglycan synthesis (left), Lipid II units carrying disaccharides are synthesized in the cytoplasm (Step 1) and exported across the cytoplasmic membrane by a flippase (MurJ) (Step 2). Subsequently, transglycosylases (TG) insert the disaccharides into a new glycan strand (Step 3). The stem peptides of the glycan strands are then cross-linked by transpeptidases (TP) to the existing peptidoglycan matrix (Step 4). Peptidoglycan hydrolysis (right) occurs due to the action of peptidoglycan hydrolases which are classified as glycosidases (glucosaminidase and muramidase), amidases or endopeptidases. The specificity of the cleavage sites of these PGH's of S. aureus are indicated by arrows.

Figure 3.

Modular structure of S. aureus peptidoglycan hydrolases. S. aureus peptidoglycan hydrolases have a modular structure. The different domains that make up these enzymes include catalytic domains, such as the amidase, glucosaminidase, CHAP, M23 peptidase and/or lytic transglycosylase domains. In addition, peptidoglycan hydrolases contain signal peptides, transmembrane domains and/or cell wall binding domains (e.g. LysM, GW) for subcellular localization.

Figure 4.

Physiological roles of S. aureus peptidoglycan hydrolases. Peptidoglycan hydrolases play different essential roles during bacterial growth and division. PGHs are involved in the entire cell cycle including cell enlargement (i), cell enlargement during septum formation (ii), daughter cell separation upon cell division (iii), and remodelling of the peptidoglycan network after daughter cell separation (iv). In addition, peptidoglycan hydrolases serve in peptidoglycan turnover (v) and they modulate cell wall passage of cell surface-located proteins (vi).

Figure 5.

Peptidoglycan hydrolase gene regulation by different transcriptional regulators. The Figure provides an overview of PGH-encoding genes of S. aureus and translational regulators that are known to modulate the PGH gene expression. Up-regulation or down-regulation by particular gene regulators are indicated in pink or olive green, respectively.