The Membrane Steps of Bacterial Cell Wall Synthesis as Antibiotic Targets

Abstract

Peptidoglycan is the major component of the cell envelope of virtually all bacteria. It has structural roles and acts as a selective sieve for molecules from the outer environment. Peptidoglycan synthesis is therefore one of the most important biogenesis pathways in bacteria and has been studied extensively over the last twenty years. The pathway starts in the cytoplasm, continues in the cytoplasmic membrane and finishes in the periplasmic space, where the precursor is polymerized into the peptidoglycan layer. A number of proteins involved in this pathway, such as the Mur enzymes and the penicillin binding proteins (PBPs), have been studied and regarded as good targets for antibiotics. The present review focuses on the membrane steps of peptidoglycan synthesis that involve two enzymes, MraY and MurG, the inhibitors of these enzymes and the inhibition mechanisms. We also discuss the challenges of targeting these two cytoplasmic membrane (associated) proteins in bacterial cells and the perspectives on how to overcome the issues.

Genomic analysis of the original Elberg Brucella melitensis Rev.1 vaccine strain reveals insights into virulence attenuation

“…In both Gram-positive and -negative bacteria, the cell wall comprises a layer of the cross-linked polymer peptidoglycan (PG), which is composed of polysaccharides with alternating N -acetylglucosamine (GlcNAc) and N- acetylmuramic acid (MurNAc) saccharide groups. PG synthesis begins in the cytoplasm, where UDP-GlcNAc is synthesized from fructose-6-phosphate by the Glm enzymes, while UDP- N -acetylmuramyl-pentapeptide is synthesized from UDP-GlcN by the Mur enzymes (MurA, MurB, MurC, MurD, MurE and MurF) [43,44]. The proteins that catalyze the final steps of the PG synthesis include the bifunctional penicillin-binding proteins (PBPs), which catalyze the polymerization of the glycan strand (transglycosylation) and the cross-linking between glycan chains (transpeptidation).…”

Влияние Эмоксипина И Мексидола На Развитие Культур Эталонных Штаммов Микроорганизмов И Их Чувствительность К Антимикробным Средствам

“…Î÷åâèäíî, ñèíåðãèçì â îòíîøåíèè àíòèáàêòåðèàëüíûõ ñðåäñòâ ÿâëÿåòñÿ îáùèì ñâîéñòâîì ïðîèçâîäíûõ 3-ãèäðîêñèïèðèäèíà, êîòîðîå âî ìíîãîì îáúÿñíÿåò ïîâûøåíèå ýôôåêòèâíîñòè àíòèìèêðîáíîé òåðàïèè ó áîëüíûõ ñ èíôåêöèîííîé ïàòîëîãèåé ïðè èõ âêëþ÷åíèè â îáùóþ ñõåìó ëå÷åíèÿ [1]. Èñõîäÿ èç ìåìáðàíîòðîïíûõ ñâîéñòâ äàííûõ ïðåïàðàòîâ [3], ìîaeíî ïðåäïîëîaeèòü, ÷òî âûÿâëåííûé ñèíåðãèçì ýìîêñèïèíà è ìåêñèäîëà â îòíîøåíèè èíãèáèòîðîâ ñèíòåçà êëåòî÷íîé ñòåíêè (öåôòàçèäèì, âàíêîìèöèí) ñâÿçàí ñ ìîäóëèðîâàíèåì ìåìáðàííûõ ýòàïîâ ýòîãî ïðîöåññà [16,17], à â îòíîøåíèè ïðåïàðàòîâ, íàðóøàþùèõ ñèíòåç áåëêà (òåòðàöèêëèí, ôóçèäèí) èëè èíãèáèòîðîâ òîïîèçîìåðàçû (íîðôëîêñàöèí), èìåþùèõ âíóòðèêëåòî÷íûå ìèøåíè, -ñ óñèëåíèåì èõ òðàíñïîðòà âíóòðü áàêòåðèàëüíîé êëåòêè ÷åðåç öèòîïëàçìàòè÷åñêóþ ìåìáðàíó [16,17]. Ñîáñòâåííîå ïðîòèâîìèêðîáíîå äåéñòâèå è ñèíåðãèçì ñ òðàäèöèîííûìè àíòèáàêòåðèàëüíûìè ñðåäñòâàìè ñëåäóåò ó÷èòûâàòü ïðè êëèíè÷åñêîì ïðèìåíåíèè ýìîêñèïèíà è ìåêñèäîëà â êîìáèíèðîâàííîé òåðàïèè èíôåêöèîííûõ çàáîëåâàíèé.…”

Structural basis for catalysis at the membrane-water interface

“…Peptidoglycan helps maintain cell shape and serves as an anchor for accessory proteins and other cell wall components. As essential components of the cell wall, enzymes contributing to the peptidoglycan biosynthetic pathway can be exploited as antibiotic targets [41, 42]. …”

“…Lipid II is then flipped across the membrane to the periplasm where its sugars are polymerized to form the glycan strands of the peptidoglycan mesh. MraY is the enzyme catalyzing the Lipid I synthesis [42]. MraY belongs to the polyprenylphosphate N -acetyl hexosamine 1-phosphate transferase (PNPT) superfamily of enzymes, which includes other potential antibiotic targets, WecA and TarO, enzymes responsible for bacterial cell wall synthesis.…”

“…Lipid I, synthesized by MraY as previously discussed, is further modified to Lipid II by the addition of a GlcNAc moiety. Lipid II is then flipped across the membrane to the periplasm where an enzyme with transglycosylase activity transfers sugars from donor Lipid II molecules to a growing glycan chain (on a Lipid II starter molecule) and the peptides are linked by an enzyme with transpeptidase activity to form the final peptidoglycan mesh [42]. TG, in the simple case, catalyzes the transfer of the disaccharide peptide unit from a donor Lipid II to an acceptor Lipid II, forming Lipid IV.…”