Targeting the Achilles' Heel of Bacteria: Different Mechanisms To Break Down the Peptidoglycan Cell Wall during Bacterial Warfare

Abstract

Bacteria commonly live in dense polymicrobial communities and compete for scarce resources. Consequently, they employ a diverse array of mechanisms to harm, inhibit, and kill their competitors. The cell wall is essential for bacterial survival by providing mechanical strength to resist osmotic stress. Because peptidoglycan is the major component of the cell wall and its synthesis is a complex multistep pathway that requires the coordinate action of several enzymes, it provides a target for rival bacteria, which have developed a large arsenal of antibacterial molecules to attack the peptidoglycan of competitors. These molecules include antibiotics, bacteriocins, and contact-dependent effectors that are either secreted into the medium or directly translocated into a target cell. In this minireview, we summarize the diversity of these molecules and highlight distinct mechanisms to disrupt the peptidoglycan, giving special attention to molecules that are known or have the potential to be used during interbacterial competitions.

Keywords: antibiotic; antimicrobial peptide; bacterial warfare; bacteriocin; effector; interbacterial competition; microbial ecology; peptidoglycan.

FIG 1

Antibiotics, bacteriocins, and effectors targeting peptidoglycan synthesis and structure. Peptidoglycan precursors UDP-N-acetylglucosamine (UDP-GlcNAc) and UDP-N-acetylmuramic acid (UDP-MurNAc) are synthesized in the cytoplasm. The enzymes MurA to MurF, Alr, and DdlA are responsible for the synthesis of UDP-MurNAc-pentapeptide, which are linked to the lipid transporter undecaprenyl phosphate, forming the intermediate lipid I. Next, UDP-GlcNAc is coupled by the enzyme MurG to form lipid II, which is flipped across the cytoplasmic membrane by the flippase MurJ. The precursor lipid II is incorporated into a glycan chain by glycosyltransferases (GTases), and the undecaprenyl pyrophosphate is recycled by the enzyme UppP. Transpeptidases (TPases) are responsible for cross-linking peptide stems of the newly polymerized glycan chain to previously synthesized chains. Antibiotics (orange boxes), bacteriocins (green boxes), and contact-dependent effectors (blue boxes) targeting the peptidoglycan either by binding and inhibition or by enzymatic cleavage are indicated. Representative molecules with similar activities are indicated by asterisks, and the complete list is described in Table 1. GlcNAc, N-acetylglucosamine; MurNAc, N-acetylmuramic acid; MurA, UDP-GlcNAc enolpyruvyl transferase; MurB, UDP-MurNAc dehydrogenase; MurC, UDP-MurNAc-l-Ala ligase; MurD, UDP-MurNAc-l-Ala-d-Glu ligase; MurE, UDP-MurNAc-l-Ala-d-Glu-mesoDAP ligase; MurF, UDP-MurNAc-tripeptide-d-alanyl-d-Ala ligase; Alr, alanine racemase; DdlA, d-Ala–d-Ala ligase A; MraY, UDP-MurNAc-pentapeptide-phosphotransferase; MurG, UDP-GlcNAc-undecaprenyl-pyrophosphoryl-MurNAc-pentapeptide transferase.

FIG 2

Chemical structures of representative classes of antibiotics that affect the peptidoglycan. (A) β-Lactams are represented by cephamycin C. (B) Glycopeptides are represented by vancomycin. (C) Cyclic peptides are depicted by plusbacin A₃. (D) Phosphoglycolipids are represented by moenomycin A. (E) Peptidyl nucleosides are represented by mureidomycin A. (F) d-Cycloserine is an analogue of d-Ala. (G) Phosphonic acids are represented by phosphonomycin. Chemical structures were drawn using ChemSketch software (Advanced Chemistry Development, Inc.).

FIG 3

The peptidoglycan intermediate lipid II is the most common target of antimicrobials. The chemical structure of lipid II was drawn using ChemSketch software (Advanced Chemistry Development, Inc.) and is represented by GlcNAc-MurNAc-pentapeptide linked to undecaprenyl pyrophosphate. The bacteriocin mersacidin, which is representing type B lantibiotics shown in Table 1, binds to GlcNAc-MurNAc and the pyrophosphate (orange ellipse). The cyclic peptide antibiotic teixobactin and the bacteriocin lacticin 3147 (type C lantibiotic) bind to MurNAc and pyrophosphate (blue ellipse). The bacteriocin nisin, which is representing type AI lantibiotics shown in Table 1, binds to the pyrophosphate moiety of lipid II (green ellipse). The cyclic lipodepsipeptide antibiotic empedopeptin binds to the pyrophosphate moiety, MurNAc, and a portion of the peptide stem (dashed ellipse). The binding site of glycopeptide antibiotics, which are represented by vancomycin, is shown by the yellow ellipse. The arrow indicates the cleavage site of the bacteriocin colicin M and the T7SS effector TelC.