Development of novel inhibitors targeting intracellular steps of peptidoglycan biosynthesis.
The widespread emergence of pathogenic bacterial strains with resistance to antibiotics is becoming a serious threat to public health. Continuous development of novel antibacterials therefore remains one of the biggest challenges to science and unmet needs in the clinics. The biosynthetic pathway of bacterial peptidoglycan, an essential building block of cell walls, has been well studied and appears to be a rich source of attractive enzyme targets for new antibacterials. We have therefore reviewed the intracellular part of peptidoglycan biosynthesis, including the enzymes GlmS, GlmM, GlmU for formation of UDP-GlcNAc, subsequent pentapeptide synthesis by MurA-MurF, and its connection to lipid carrier by MraY and MurG. Naturally occurring inhibitors and the development of low-molecular weight inhibitors of the intracellular part of peptidoglycan synthesis are presented.
Kotnik
Miha
M
Lek Pharmaceuticals d.d., Drug Discovery, Ljubljana, Slovenia.
Anderluh
Petra Stefanic
PS
Prezelj
Andrej
A
D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008025:Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D008970:Molecular Weight; D010457:Peptidoglycan / Q000096:biosynthesis*; D014176:Protein Biosynthesis / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D010457:Peptidoglycan; D000591:Amino Acid Isomerases; D008025:Ligases