Therapeutic compounds targeting Lipid II for antibacterial purposes

Infection and Drug Resistance Dovepress open access to scientific and medical research Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 82.251.157.115 on 11-Jul-2020 For personal use only. Open Access Full Text Article Therapeutic compounds targeting Lipid II for antibacterial purposes This article was published in the following Dove Press journal: Infection and Drug Resistance Jakob J Malin 1,2 Erik de Leeuw 3 1 University of Cologne, Department I of Internal Medicine, Division of Infectious Diseases, Cologne, Germany; 2Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; 3Institute of Human Virology and Department of Molecular Biology & Biochemistry of the University of Maryland, Baltimore School of Medicine, Baltimore, MD 21201, USA Abstract: Resistance against commonly used antibiotics has emerged in all bacterial pathogens. In fact, there is no antibiotic currently in clinical use against which resistance has not been reported. In particular, rapidly increasing urbanization in developing nations are sites of major concern. Additionally, the widespread practice by physicians to prescribe antibiotics in cases of viral infections puts selective pressure on antibiotics that still remain effective and it will only be a matter of time before resistance develops on a large scale. The biosynthesis pathway of the bacterial cell wall is well studied and a validated target for the development of antibacterial agents. Cell wall biosynthesis involves two major processes; 1) the biosynthesis of cell wall teichoic acids and 2) the biosynthesis of peptidoglycan. Key molecules in these pathways, including enzymes and precursor molecules are attractive targets for the development of novel antibacterial agents. In this review, we will focus on the major class of natural antibacterial compounds that target the peptidoglycan precursor molecule Lipid II; namely the glycopeptides, including the novel generation of lipoglycopeptides. We will discuss their mechanism-of-action and clinical applications. Further, we will briefly discuss additional peptides that target Lipid II such as the lantibiotic nisin and defensins. We will highlight recent developments and future perspectives. Keywords: antimicrobial peptides, Lipid II, bacterial cell wall, antibiotics Introduction Bacterial cell wall assembly Correspondence: Erik de Leeuw Institute of Human Virology, University of Maryland Baltimore School of Medicine, 725 West Lombard Street, Baltimore, MD 21201, USA Tel +1 410 706 3430 Fax +1 410 706 7583 Email The cell wall of both Gram-negative and -positive bacteria comprises a peptidoglycan layer which is composed of a polymer of alternating amino sugars, N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc). Cross-linking of the polymer chains by pentapeptides achieves mechanical strength and structural integrity of the cell.1 In addition to that it protects the cell from osmotic stress. Inhibition of peptidoglycan biosynthesis inhibits cell growth. This makes the assembly and maintenance of the peptidoglycan polymer a commonly used target for antibiotics. Figure 1 illustrates membrane events in the biosynthesis of the peptidoglycan layer. On the cytoplasmic side of the plasma membrane first the soluble precursor UDPMurNAc-pentapeptide is linked to the membrane carrier bactoprenol-phosphate (C55P) yielding Lipid I. In a second step GlcNac is added by the enzyme MurG to yield Lipid II.3–5 In preparation for building interpeptide bridges between individual Lipid II molecules additional amino acids are added to the pentapeptide by Fem ligases (eg Gly in case of S. aureus).2 Lipid II is then translocated along the membrane to the peripheral side by a not well understoodmechanism.Recent binding studies suggest that this process might be 2613 submit your manuscript | www.dovepress.com Infection and Drug Resistance 2019:12 2613–2625 DovePress © 2019 Malin and de Leeuw. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/ terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). http://doi.org/10.2147/IDR.S215070 Powered by TCPDF (www.tcpdf.org) REVIEW Dovepress Malin and de Leeuw Transglycosylation Transpeptidation M G Cell surface M G M G M G M G M G M G M G M G M G M G M G M G M G (lipo-) glycopeptides (e.g. vancomycin, teicoplanin, telavancin) G G M G BAS00127538 M Mersacidin? M G M Phospholipid bilayer G Lantibiotics Katanosin B Plusbacin A3 Mannopeptomycines Ramoplanin Plectasin Teixobactin Flippase (MurJ / RodA / FtsW) MraY M MurG G M Fem ligases G M UDP UMP M G UDP (AA-tRNA)n tRNA M MurNAc G GlcNAc Phosphate Pentapeptide UDP C55-P Amino acids (AA) * Figure 1 Membrane bound processes in the bacterial cell wall biosynthesis cycle. Lipid II binding antibiotics are shown corresponding to the step in the cycle that they inhibit. Note: *varying per species.2 Abbreviations: G, N-acetyl glucosamine; M, N-acetyl muramic acid; MraY, phospho-MurNAc-pentapeptide translocase; MurG, Undecaprenyldiphospho-muramoylpentapeptide beta-N-acetylglucosaminyltransferase; UMP, uridine monophosphate; UDP, uridine diphosphate. mediated by the flippase enzyme MurJ.6 However, other candidates including RodA and FtsW have been suggested.7,8 On the periplasmic side penicillin-binding proteins (PBPs) catalyze the incorporation of the peptidoglycan unit into the growing cell wall. Class A PBPs obtain insertion of the MurNAcpeptide-GlcNAc subunit into the nascent peptidoglycan layer (transglycosylation) before the peptidoglycan chains are linked together by the formation of peptide crossbridges through the action of both class A - and B PBPs (transpeptidation).9 The remaining complex of lipid anchor and pyrophosphate is shuttled back to the cytosolic side. It can then be reused for following Lipid II synthesis.3 The amount of Lipid II that can be synthesized is limited by the small amount of bactoprenyl phosphate that is available on the cytosolic membrane. About 2×105 molecules C55P per cell have to provide for the enduring synthesis of around 20 peptidoglycan layers in Gram-positive and 1.5 in Gram-negative bacteria.10,11 This is achieved by a high 2614 Powered by TCPDF (www.tcpdf.org) G M Cytoplasm Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 82.251.157.115 on 11-Jul-2020 For personal use only. 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