Antibiotic Targets in Gonococcal Cell Wall Metabolism

Abstract

The peptidoglycan cell wall that encloses the bacterial cell and provides structural support and protection is remodeled by multiple enzymes that synthesize and cleave the polymer during growth. This essential and dynamic structure has been targeted by multiple antibiotics to treat gonococcal infections. Up until now, antibiotics have been used against the biosynthetic machinery and the therapeutic potential of inhibiting enzymatic activities involved in peptidoglycan breakdown has not been explored. Given the major antibiotic resistance problems we currently face, it is crucial to identify other possible targets that are key to maintaining cell integrity and contribute to disease development. This article reviews peptidoglycan as an antibiotic target, how N. gonorrhoeae has developed resistance to currently available antibiotics, and the potential of continuing to target this essential structure to combat gonococcal infections by attacking alternative enzymatic activities involved in cell wall modification and metabolism.

Keywords: Neisseria gonorrhoeae; lytic transglycosylase; peptidoglycan.

Figure 1

Cleavage site of gonococcal peptidoglycanases. Lytic transglycosylases cleave the β-1,-4 link between the N-acetylmuramic acid (MurNAc) and N-acetylglucosamine (GlcNAc) sugar moieties. DD-carboxypeptidases and a LD-carboxypeptidase shorten the peptide stem. The LD-carboxypeptidase can only act on four amino acid peptide stems. An N-acetylmuramyl L-alanine amidase cleaves the stem off the MurNAc residue. Endopeptidases cut the crosslinks between peptide chains from adjacent PG strands. A PG de-O-deacetylase removes the O-acetyl group from MurNAc. Without de-acetylation, the lytic trans-glycosylases cannot cleave the MurNAc bond.