Breaking down the cell wall: Still an attractive antibacterial strategy

Abstract

Since the advent of penicillin, humans have known about and explored the phenomenon of bacterial inhibition via antibiotics. However, with changes in the global environment and the abuse of antibiotics, resistance mechanisms have been selected in bacteria, presenting huge threats and challenges to the global medical and health system. Thus, the study and development of new antimicrobials is of unprecedented urgency and difficulty. Bacteria surround themselves with a cell wall to maintain cell rigidity and protect against environmental insults. Humans have taken advantage of antibiotics to target the bacterial cell wall, yielding some of the most widely used antibiotics to date. The cell wall is essential for bacterial growth and virulence but is absent from humans, remaining a high-priority target for antibiotic screening throughout the antibiotic era. Here, we review the extensively studied targets, i.e., MurA, MurB, MurC, MurD, MurE, MurF, Alr, Ddl, MurI, MurG, lipid A, and BamA in the cell wall, starting from the very beginning to the latest developments to elucidate antimicrobial screening. Furthermore, recent advances, including MraY and MsbA in peptidoglycan and lipopolysaccharide, and tagO, LtaS, LspA, Lgt, Lnt, Tol-Pal, MntC, and OspA in teichoic acid and lipoprotein, have also been profoundly discussed. The review further highlights that the application of new methods such as macromolecular labeling, compound libraries construction, and structure-based drug design will inspire researchers to screen ideal antibiotics.

Negative regulation of MurZ and MurA underlies the essentiality of GpsB‐ and StkP‐mediated protein phosphorylation in Streptococcus pneumoniaeD39

“…(1-carboxyvinyl)-alpha-D-glucosamine in the first committed step in the synthesis of the PG precursor Lipid II (Brown et al, 1995;Zhou et al, 2022). Like other low-GC Gram-positive bacteria, S. pneumoniae encodes two distinct homologs of this enzyme (Figure 1) (Blake et al, 2009;Chan et al, 2022;Du et al, 2000;Kedar et al, 2008;Kock et al, 2004;Mascari et al, 2022;Vesic & Kristich, 2012).…”

“…Besides phpP null mutations, Δ gpsB ( Spn ) was suppressed by two large chromosomal duplications that also contained deletions (Rued et al, 2017). Notably, these duplications contain murZ (Rued et al, 2017; Wamp et al, 2020), which encodes one of two homologs of the UDP‐N‐acetylglucosamine 1‐carboxyvinyltransferase that converts PEP and UDP‐GlcNAc to Pi and UDP‐N‐acetyl‐3‐O‐(1‐carboxyvinyl)‐alpha‐D‐glucosamine in the first committed step in the synthesis of the PG precursor Lipid II (Brown et al, 1995; Zhou et al, 2022). Like other low‐GC Gram‐positive bacteria, S. pneumoniae encodes two distinct homologs of this enzyme (Figure 1) (Blake et al, 2009; Chan et al, 2022; Du et al, 2000; Kedar et al, 2008; Kock et al, 2004; Mascari et al, 2022; Vesic & Kristich, 2012).…”

“…The two homologs in S. pneumoniae strains were annotated as MurZ (MurA2) (Spd_0967) and MurA (MurA1) ( Spn )(Spd_1764) (Hoskins et al, 2001) (Figure 1). The MurA‐family homolog, which is the sole enzyme present in Gram‐negative bacteria (Brown et al, 1995; Du et al, 2000; Hummels et al, 2023; Zhou et al, 2022), often plays a predominant enzymatic role in Gram‐positive bacteria and is essential in B. subtilis , B. anthracis , and L. monocytogenes (Kedar et al, 2008; Kock et al, 2004; Rismondo et al, 2017), and required for normal growth of E. faecalis and S. aureus (Blake et al, 2009; Mascari et al, 2022; Vesic & Kristich, 2012). MurZ( Spn ) and MurA( Spn ) have a synthetic lethal relationship, where one homolog functions in the absence of the other, but both homologs cannot be deleted in the same strain(Du et al, 2000).…”

Chromosomal Duplications of MurZ (MurA2) or MurA (MurA1), Amino Acid Substitutions in MurZ (MurA2), and Absence of KhpAB Obviate the Requirement for Protein Phosphorylation inStreptococcus pneumoniaeD39

“…Besides phpP null mutations, Δ gpsB ( Spn ) was suppressed by two large chromosomal duplications that also contained deletions (Rued et al ., 2017). Notably, these duplications contain murZ (Rued et al ., 2017, Wamp et al ., 2020), which encodes one of two homologs of the UDP-N-acetylglucosamine 1-carboxyvinyltransferase that converts PEP and UDP-GlcNAc to Pi and UDP-N-acetyl-3-O-(1-carboxyvinyl)-alpha-D-glucosamine in the first committed step in the synthesis of the PG precursor Lipid II (Brown et al ., 1995, Zhou et al ., 2022). Like other low-GC Gram-positive bacteria, S. pneumoniae encodes two distinct homologs of this enzyme (Fig.…”

“…1). The MurA-family homolog, which is the sole enzyme present in Gram-negative bacteria (Brown et al ., 1995, Du et al ., 2000, Hummels et al ., 2023, Zhou et al ., 2022), often plays a predominant enzymatic role in Gram-positive bacteria and is essential in B. subtilis , B. anthracis , and L. monocytogenes (Kock et al ., 2004, Kedar et al ., 2008, Rismondo et al ., 2017), and required for normal growth of E. faecalis and S. aureus (Vesic & Kristich, 2012, Blake et al ., 2009, Mascari et al ., 2022). MurZ( Spn ) and MurA( Spn ) have a synthetic lethal relationship, where one homolog functions in the absence of the other, but both homologs cannot be deleted in the same strain(Du et al ., 2000).…”