uridine-diphosphate-n-acetylmuramic-acid and Gram-Positive-Bacterial-Infections

Antimicrobial peptides (AMPs) are natural antibiotics produced by virtually all living organisms. Typically, AMPs are cationic and amphiphilic and first contacts with target microbes involve interactions with negatively charged components of the cell envelope such as lipopolysaccharide (LPS), and wall- or lipoteichoic acids (WTA, LTA). The importance of charge-mediated interactions of AMPs with the cell envelope is reflected by effective microbial resistance mechanisms which are based on reduction of the overall charge of these polymers. The anionic polymers are linked in various ways to the stress-bearing polymer of the cell envelope, the peptidoglycan, which is made of a highly conserved building block, a disaccharide-pentapeptide moiety that also contains charged residues. This structural element, in spite of its conservation throughout the bacterial world, can undergo genus- and species-specific modifications that also impact significantly on the overall charge of the cell envelope and on the binding affinity of AMPs. The modification reactions involved largely occur on the membrane-bound peptidoglycan building block, the so-called lipid II, which is a most prominent target for AMPs. In this review, we focus on modifications of lipid II and peptidoglycan and discuss their consequences for the interactions with various classes of AMPs, such as defensins, lantibiotics and glyco-(lipo)-peptide antibiotics. This article is part of a Special Issue entitled: Bacterial Resistance to Antimicrobial Peptides.

Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Cell Wall; Drug Resistance, Bacterial; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Host-Pathogen Interactions; Humans; Microbial Viability; Models, Molecular; Molecular Structure; Protein Binding; Signal Transduction; Structure-Activity Relationship; 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

Cell wall antibiotics are crucial for combatting the emerging wave of resistant bacteria. Yet, our understanding of antibiotic action is limited, as many strains devoid of all resistance determinants display far higher antibiotic tolerance in vivo than suggested by the antibiotic-target binding affinity in vitro. To resolve this conflict, here we develop a comprehensive theory for the bacterial cell wall biosynthetic pathway and study its perturbation by antibiotics. We find that the closed-loop architecture of the lipid II cycle of wall biosynthesis features a highly asymmetric distribution of pathway intermediates, and show that antibiotic tolerance scales inversely with the abundance of the targeted pathway intermediate. We formalize this principle of minimal target exposure as intrinsic resistance mechanism and predict how cooperative drug-target interactions can mitigate resistance. The theory accurately predicts the in vivo efficacy for various cell wall antibiotics in different Gram-positive bacteria and contributes to a systems-level understanding of antibiotic action.

Topics: Biosynthetic Pathways; Cell Wall; Drug Resistance, Bacterial; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Models, Biological; Uridine Diphosphate N-Acetylmuramic Acid

The partial genome sequencing of Bacillus amyloliquefaciens GA1 led to the identification of the aml gene cluster involved in the synthesis of the novel lantibiotic named amylolysin. Pure amylolysin was shown to have an antibacterial activity toward Gram-positive bacteria including methicillin resistant Staphylococcus aureus. The lantibiotic was also found efficient to inhibit the growth of Listeria monocytogenes strains on poultry meat upon a long storage at 4°C. In silico analyses of the aml gene cluster revealed the presence of a characteristic motif involved in interaction with peptidoglycan precursor lipid II. In the present work, this interaction was further investigated using the LiaRS based reporter gene that is able to sense specifically antibiotics that interfere with lipid II cycle. Beside this, the pore-forming ability of amylolysin was evidenced by means of membrane depolarization measurements and cell leaking experiments.

Topics: Animals; Anti-Bacterial Agents; Bacillus; Bacteriocins; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Listeria monocytogenes; Listeriosis; Multigene Family; Poultry; Uridine Diphosphate N-Acetylmuramic Acid

Antimicrobial peptides are a new class of antibiotics that are promising for pharmaceutical applications because they have retained efficacy throughout evolution. One class of antimicrobial peptides are the defensins, which have been found in different species. Here we describe a new fungal defensin, eurocin. Eurocin acts against a range of Gram-positive human pathogens but not against Gram-negative bacteria. Eurocin consists of 42 amino acids, forming a cysteine-stabilized α/β-fold. The thermal denaturation data point shows the disulfide bridges being responsible for the stability of the fold. Eurocin does not form pores in cell membranes at physiologically relevant concentrations; it does, however, lead to limited leakage of a fluorophore from small unilamellar vesicles. Eurocin interacts with detergent micelles, and it inhibits the synthesis of cell walls by binding equimolarly to the cell wall precursor lipid II.

Topics: Anti-Infective Agents; Defensins; Eurotium; Fungal Proteins; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Membrane Lipids; Micelles; Protein Folding; Protein Structure, Secondary; Uridine Diphosphate N-Acetylmuramic Acid