uridine-diphosphate-n-acetylmuramic-acid and bactoprenol

Targeting the bactoprenol-coupled cell wall precursor lipid II is a validated antibacterial strategy. In this review, selected prototype lipid II-binding antibiotics of different chemical classes are discussed. Although these compounds attack the same molecular target, they trigger nuanced and diverse cellular effects. Consequently, the mechanisms of antibacterial resistance and the likelihood of resistance development may vary substantially.

Topics: Anti-Bacterial Agents; Bacteria; Cell Wall; Drug Resistance, Bacterial; Terpenes; Uridine Diphosphate N-Acetylmuramic Acid

Bacterial cell wall biosynthesis represents an antibiotic target pathway for therapeutic intervention. An increasing number of natural antibiotic compounds have been demonstrated to inhibit the membrane-associated steps of cell wall biosynthesis by targeting bactoprenol-mediated precursor cycling, particularly at the stage of the completed building block Lipid II. These antibiotic compounds belong to various chemical classes including glycopeptides, lipopeptides and lipodepsipeptides, and lantibiotics and other antimicrobial peptides. The clinical success of vancomycin in the treatment of multiresistant Gram-positive bacteria has stimulated further development of glycopeptide antibiotics and research of other Lipid II-binding compounds. The state-of-the-art in the targeting of cell wall precursors is summarized in this review.

Topics: Anti-Bacterial Agents; Cell Wall; Drug Delivery Systems; Drug Resistance, Multiple, Bacterial; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Terpenes; Uridine Diphosphate N-Acetylmuramic Acid; Vancomycin

Friulimicin B is a naturally occurring cyclic lipopeptide, produced by the actinomycete Actinoplanes friuliensis, with excellent activity against gram-positive pathogens, including multidrug-resistant strains. It consists of a macrocyclic decapeptide core and a lipid tail, interlinked by an exocyclic amino acid. Friulimicin is water soluble and amphiphilic, with an overall negative charge. Amphiphilicity is enhanced in the presence of Ca(2+), which is also indispensable for antimicrobial activity. Friulimicin shares these physicochemical properties with daptomycin, which is suggested to kill gram-positive bacteria through the formation of pores in the cytoplasmic membrane. In spite of the fact that friulimicin shares features of structure and potency with daptomycin, we found that friulimicin has a unique mode of action and severely affects the cell envelope of gram-positive bacteria, acting via a defined target. We found friulimicin to interrupt the cell wall precursor cycle through the formation of a Ca(2+)-dependent complex with the bactoprenol phosphate carrier C(55)-P, which is not targeted by any other antibiotic in use. Since C(55)-P also serves as a carrier in teichoic acid biosynthesis and capsule formation, it is likely that friulimicin blocks multiple pathways that are essential for a functional gram-positive cell envelope.

Topics: Anti-Bacterial Agents; Bacillus subtilis; Cell Wall; Microbial Sensitivity Tests; Peptides; Staphylococcus; Terpenes; Uridine Diphosphate N-Acetylmuramic Acid