Core Steps of Membrane-Bound Peptidoglycan Biosynthesis: Recent Advances, Insight and Opportunities

Abstract

We are entering an era where the efficacy of current antibiotics is declining, due to the development and widespread dispersion of antibiotic resistance mechanisms. These factors highlight the need for novel antimicrobial discovery. A large number of antimicrobial natural products elicit their effect by directly targeting discrete areas of peptidoglycan metabolism. Many such natural products bind directly to the essential cell wall precursor Lipid II and its metabolites, i.e., preventing the utlisation of vital substrates by direct binding rather than inhibiting the metabolising enzymes themselves. Concurrently, there has been an increase in the knowledge surrounding the proteins essential to the metabolism of Lipid II at and across the cytoplasmic membrane. In this review, we draw these elements together and look to future antimicrobial opportunities in this area.

Suppression of a deletion mutation in the gene encoding essential PBP2b reveals a new lytic transglycosylase involved in peripheral peptidoglycan synthesis in Streptococcus pneumoniae D39

“…Given its potential as a target for future antibiotic discovery and its role in resistance development to current antibiotics, it is important to understand the mechanisms of PG biosynthesis in differently shaped pathogenic bacteria (Sham et al ., ; den Blaauwen et al ., ; Teo and Roper, ). To form ellipsoid‐shaped cells, S. pneumoniae and other ovococcus bacteria require two modes of PG synthesis: septal PG synthesis to divide cells and a form of side‐wall (peripheral) PG synthesis to elongate cells (Supporting Information Fig.…”

Analysis of SMALP co-extracted phospholipids shows distinct membrane environments for three classes of bacterial membrane protein

“…ZipA is a bitopic membrane protein harbouring a short N-terminal transmembrane helix 2 , whereas FtsA is thought to attach peripherally to the cell membrane by a short C-terminal amphipathic helix motif 3 . Another important membrane protein, PgpB, is an integral membrane lipid phosphatase with a key role in membrane biosynthesis by generation of phosphatidylglycerol (PG), but additionally with the ability to dephosphorylate the glycan lipid carrier undecaprenyl pyrophosphate 4 . The activity of PgpB depends on the acyl chain length of the lipid substrates and has been reported to be partially inhibited by the zwitterionic phospholipid phosphatidylethanolamine (PE), leading to the suggestion that PE acts as a regulator of PgpB activity to balance the amount of zwitterionic and anionic phospholipids in the membrane necessary for the survival and growth of E .…”

Cardiolipin Alters Rhodobacter sphaeroides Cell Shape by Affecting Peptidoglycan Precursor Biosynthesis

“…The shape of bacteria arises from the morphology of the cell wall and specifically from the layer of peptidoglycan (PG) surrounding the cytoplasmic membrane that resists osmotic pressure and other mechanical forces applied to cells (3, 4). Researchers in the field of antibiotic development have paid acute attention to the underlying machinery controlling PG assembly and the catastrophic effect of inhibiting its biosynthesis (5, 6). PG is synthesized in three distinct steps in Gram-negative bacteria (Fig.…”