uridine-diphosphate-n-acetylmuramic-acid and teixobactin

Natural product antibiotics usually target the major biosynthetic pathways of bacterial cells and the search for new targets outside these pathways has proven very difficult. Cell wall biosynthesis maybe the most prominent antibiotic target, and ß-lactams are among the clinically most relevant antibiotics. Among cell wall biosynthesis inhibitors, glycopeptide antibiotics are a second group of important drugs, which bind to the peptidoglycan building block lipid II and prevent the incorporation of the monomeric unit into polymeric cell wall. However, lipid II acts as a docking molecule for many more naturally occurring antibiotics from diverse chemical classes and likely is the most targeted molecule in antibacterial mechanisms. We summarize current knowledge on lipid II binding antibiotics and explain, on the levels of mechanisms and resistance development, why lipid II is such a prominent target, and thus provide insights for the design of new antibiotic drugs.

Topics: Anti-Bacterial Agents; Bacteria; Bacteriocins; Biological Products; Biosynthetic Pathways; Cell Wall; Defensins; Depsipeptides; Drug Resistance, Bacterial; Glycopeptides; Molecular Docking Simulation; Peptidoglycan; Uridine Diphosphate N-Acetylmuramic Acid; Vancomycin

Understanding the mode of action of antibiotics is becoming more and more important in the time that microorganisms start to develop resistance. One very well validated target of several classes of antibiotics is the peptidoglycan precursor lipid II. In this review different classes of lipid II targeting antibiotics will be discussed in detail, including the lantibiotics, human invertebrate defensins and the recently discovered teixobactin. By hitting bacteria where it hurts, at the level of lipid II, we expect to be able to develop efficient antibacterial agents in the future. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert.

Topics: Amino Acid Sequence; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Bacillus subtilis; Bacteriocins; Defensins; Depsipeptides; Escherichia coli; Lactococcus lactis; Molecular Docking Simulation; Molecular Sequence Data; Peptidoglycan; Staphylococcus; Streptomyces; Uridine Diphosphate N-Acetylmuramic Acid

Research into antibacterial agents has recently gathered pace in light of the disturbing crisis of antimicrobial resistance. The development of modern tools offers the opportunity of reviving the fallen era of antibacterial discovery through uncovering novel lead compounds that target vital bacterial cell components, such as lipid II. This paper provides a summary of the role of lipid II as well as an overview and insight into the structural features of macrocyclic peptides that inhibit this bacterial cell wall component. The recent discovery of teixobactin, a new class of lipid II inhibitor has generated substantial research interests. As such, the significant progress that has been achieved towards its development as a promising antibacterial agent is discussed.

Topics: Anti-Bacterial Agents; Bacteria; Cell Wall; Depsipeptides; Uridine Diphosphate N-Acetylmuramic Acid

The prevalence of life-threatening, drug-resistant microbial infections has challenged researchers to consider alternatives to currently available antibiotics. Teixobactin is a recently discovered "resistance-proof" antimicrobial peptide that targets the bacterial cell wall precursor lipid II. In doing so, teixobactin exhibits potent antimicrobial activity against a wide range of Gram-positive organisms. Herein we demonstrate that teixobactin and several structural analogues are capable of binding lipid II from both Gram-positive and Gram-negative bacteria. Furthermore, we show that when combined with known outer membrane-disrupting peptides, teixobactin is active against Gram-negative organisms.

Topics: Anti-Bacterial Agents; Binding Sites; Cell Wall; Depsipeptides; Gram-Negative Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests; Molecular Conformation; Uridine Diphosphate N-Acetylmuramic Acid

The natural antibiotic teixobactin kills pathogenic bacteria without detectable resistance. The difficult synthesis and unfavourable solubility of teixobactin require modifications, yet insufficient knowledge on its binding mode impedes the hunt for superior analogues. Thus far, teixobactins are assumed to kill bacteria by binding to cognate cell wall precursors (Lipid II and III). Here we present the binding mode of teixobactins in cellular membranes using solid-state NMR, microscopy, and affinity assays. We solve the structure of the complex formed by an improved teixobactin-analogue and Lipid II and reveal how teixobactins recognize a broad spectrum of targets. Unexpectedly, we find that teixobactins only weakly bind to Lipid II in cellular membranes, implying the direct interaction with cell wall precursors is not the sole killing mechanism. Our data suggest an additional mechanism affords the excellent activity of teixobactins, which can block the cell wall biosynthesis by capturing precursors in massive clusters on membranes.

Topics: Anti-Bacterial Agents; Cell Membrane; Cell Wall; Depsipeptides; Liposomes; Magnetic Resonance Spectroscopy; Microscopy, Fluorescence; Molecular Structure; Structure-Activity Relationship; Uridine Diphosphate N-Acetylmuramic Acid

Ever since the discovery of the new antibiotic teixobactin, studies of its structure-activity relationships have never ceased. Here we focus on the chirality of the threonine (Thr) residue, which belongs to the ring motif of teixobactin and plays an important role in the binding with its target, lipid II molecule. We study the structural propensity of the open and closed ring motifs with different chiral Thr residues as well as the teixobactin-lipid II complex with the help of molecular dynamics simulations. Our results suggest that different chiralities lead to different NH orientations of Thr with respect to the ring plane. Only in the closed ring motif with d-Thr is a favored binding cavity achievable with all four NH groups facing the same side of the ring plane. This study develops a deeper understanding of the binding mechanism of teixobactin and lipid II and is expected to be beneficial to new teixobactin-based drug design.

Topics: Amino Acid Motifs; Anti-Bacterial Agents; Depsipeptides; Molecular Dynamics Simulation; Protein Conformation; Threonine; Uridine Diphosphate N-Acetylmuramic Acid

Topics: Anti-Bacterial Agents; Depsipeptides; Drug Discovery; Drug Resistance, Multiple, Bacterial; Humans; Methicillin-Resistant Staphylococcus aureus; Mycobacterium tuberculosis; Peptides; Uridine Diphosphate N-Acetylmuramic Acid; Vancomycin-Resistant Enterococci

Lipid II, a peptidoglycan, is a precursor in bacterial cell synthesis. It has both hydrophilic and lipophilic properties. The molecule translocates a bacterial membrane to deliver and incorporate "building blocks" from disaccharide-pentapeptide into the peptidoglican wall. Lipid II is a valid antibiotic target. A receptor binding pocket may be occupied by a ligand in various plausible conformations, among which only few ones are energetically related to a biological activity in the physiological efficiency domain. This paper reports the mapping of the conformational space of Lipid II in its interaction with Teixobactin and other Lipid II ligands.. In order to study computationally the complex between Lipid II and ligands, a docking study was first carried on. Docking site was retrieved form literature. After docking, 5 ligand conformations and further 5 complexes (denoted 00 to 04) for each molecule were taken into account. For each structure, conformational studies were performed. Statistical analysis, conformational analysis and molecular dynamics based clustering were used to predict the potency of these compounds. A score for potency prediction was developed.. Appling lipid II classification according to Lipid II conformational energy, a conformation of Teixobactin proved to be energetically favorable, followed by Oritravicin, Dalbavycin, Telvanicin, Teicoplamin and Vancomycin, respectively. Scoring of molecules according to cluster band and PCA produced the same result. Molecules classified according to standard deviations showed Dalbavycin as the most favorable conformation, followed by Teicoplamin, Telvanicin, Teixobactin, Oritravicin and Vancomycin, respectively. Total score showing best energetic efficiency of complex formation shows Teixobactin to have the best conformation (a score of 15 points) followed by Dalbavycin (14 points), Oritravicin (12v points), Telvanicin (10 points), Teicoplamin (9 points), Vancomycin (3 points).. Statistical analysis of conformations can be used to predict the efficiency of ligand - target interaction and consecutively to find insight regarding ligand potency and postulate about favorable conformation of ligand and binding site. In this study it was shown that Teixobactin is more efficient in binding with Lipid II compared to Vancomycin, results confirmed by experimental data reported in literature.

Topics: Binding Sites; Depsipeptides; Ligands; Models, Molecular; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Conformation; Uridine Diphosphate N-Acetylmuramic Acid

Teixobactin, targeting lipid II, represents a new class of antibiotics with novel structures and has excellent activity against Gram-positive pathogens. We developed a new convergent method to synthesize a series of teixobactin analogues and explored structure-activity relationships. We obtained equipotent and simplified teixobactin analogues, replacing the l- allo-enduracididine with lysine, substituting oxygen to nitrogen on threonine, and adding a phenyl group on the d-phenylalanine. On the basis of the antibacterial activities that resulted from corresponding modifications of the d-phenylalanine, we propose a hydrophobic interaction between lipid II and the N-terminal of teixobactin analogues, which we map out with our analogue 35. Finally, a representative analogue from our series showed high efficiency in a mouse model of Streptococcus pneumoniae septicemia.

Topics: Animals; Anti-Bacterial Agents; Depsipeptides; Female; Hydrophobic and Hydrophilic Interactions; Methicillin-Resistant Staphylococcus aureus; Mice, Inbred C57BL; Microbial Sensitivity Tests; Molecular Structure; Sepsis; Streptococcus pneumoniae; Streptococcus pyogenes; Structure-Activity Relationship; Uridine Diphosphate N-Acetylmuramic Acid; Vancomycin-Resistant Enterococci