Structure–activity exploration of a small-molecule Lipid II inhibitor

Drug Design, Development and Therapy Dovepress open access to scientific and medical research Original Research Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 37.59.46.207 on 12-Jul-2018 For personal use only. Open Access Full Text Article Structure–activity exploration of a small-molecule Lipid II inhibitor This article was published in the following Dove Press journal: Drug Design, Development and Therapy 24 April 2015 Number of times this article has been viewed Steven Fletcher 1 Wenbo Yu 1,2 Jing Huang 1,2 Steven M Kwasny 3 Jay Chauhan 1 Timothy J Opperman 3 Alexander D MacKerell Jr 1,2 Erik PH de Leeuw 4 Department of Pharmaceutical Sciences, 2Computer-Aided Drug Design Center, University of Maryland, School of Pharmacy, Baltimore, MD, 3Microbiotix, Inc., Worcester, MA, 4Institute of Human Virology and Department of Biochemistry and Molecular Biology, University of Maryland, School of Medicine, Baltimore, MD, USA 1 Correspondence: Erik PH de Leeuw Institute of Human Virology and Department of Biochemistry and Molecular Biology, University of Maryland, School of Medicine, 725 West Lombard Street, Baltimore, MD 21201, USA Tel +1 410 706 1970 Fax +1 410 706 7583 Email Introduction With the rapid increase of antibiotic resistance, there is an urgent need to develop novel classes of potent antibiotics against established molecular targets. Lipid II is essential for cell wall biosynthesis, synthesized in limited amounts,1 and has a high turnover rate, which makes it an established molecular target for antibiotics.2,3 Four different classes of peptide antibiotics that target Lipid II have been described: (1) the glycopeptides, including vancomycin and teicoplanin; (2) the depsipeptide antibiotics, including ramoplanin and enduracidins; (3) the lantibiotics, including nisin and mersacidin; and (4) cyclic peptides, including mannopeptimycins, plusbacin, and katanosin B.1,4–9 Strikingly, these molecules do not share any obvious sequence homology or structural similarity, yet all are able to specifically interact with Lipid II in the bacterial membrane environment. The glycopeptide antibiotic vancomycin was the first compound discovered to kill bacteria by targeting Lipid II. Currently, vancomycin serves as a principal treatment for infections caused by all major Gram-positive pathogens including methicillin-resistant Staphylococcus aureus (MRSA). However, resistance to vancomycin is increasing, and a number of vancomycin-insensitive strains have been described.10 We recently reported on the functional interaction between Lipid II and defensins, a major family of natural antimicrobial peptides that protect the host’s epithelial surfaces against microbial invasion.11,12 Several studies on defensins from other species, including fungi,13 invertebrates,14 and human,15 have firmly established Lipid II as a target for this class of natural antimicrobial peptides. Based on the interaction between Lipid II and human neutrophil peptide-1, we identified low-molecular weight synthetic 2383 submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2015:9 2383–2394 Dovepress © 2015 Fletcher et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php http://dx.doi.org/10.2147/DDDT.S79504 Powered by TCPDF (www.tcpdf.org) Abstract: We have recently identified low-molecular weight compounds that act as inhibitors of Lipid II, an essential precursor of bacterial cell wall biosynthesis. Lipid II comprises specialized lipid (bactoprenol) linked to a hydrophilic head group consisting of a peptidoglycan subunit (N-acetyl glucosamine [GlcNAc]–N-acetyl muramic acid [MurNAc] disaccharide coupled to a short pentapeptide moiety) via a pyrophosphate. One of our lead compounds, a diphenyltrimethyl indolene pyrylium, termed BAS00127538, interacts with the MurNAc moiety and the isoprenyl tail of Lipid II. Here, we report on the structure–activity relationship of BAS00127538 derivatives obtained by in silico analyses and de novo chemical synthesis. Our results indicate that Lipid II binding and bacterial killing are related to three features: the diphenyl moiety, the indolene moiety, and the positive charge of the pyrylium. Replacement of the pyrylium moiety with an N-methyl pyridinium, which may have importance in stability of the molecule, did not alter Lipid II binding or antibacterial potency. Keywords: computer-aided drug design, Lipid II, antibiotics, phospholipid Dovepress Fletcher et al Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 37.59.46.207 on 12-Jul-2018 For personal use only. compounds that target Lipid II with high specificity and affinity.16 One of our lead compounds, BAS00127538, was characterized further and revealed a unique interaction with Lipid II that differs from antibiotics currently in clinical use or development. In this study, we report on the structural and functional relationships of derivatives of BAS00127538. Materials and methods Materials and bacterial strains S. aureus ATCC 29213, Escherichia coli ATCC 25922, Enterococcus faecalis ATCC 29212, Streptococcus pneumonia ATCC 49619, and Acinetobacter baumannii ATCC 19606 were obtained from Microbiologics (St Cloud, MN, USA). S. aureus USA300 (MRSA), S. aureus ATCC (vancomycin intermediate-resistant S. aureus), and S. aureus NTS (vancomycin intermediate-resistant S. aureus) were generously provided by the Laboratory of Pathology, University of Maryland, School of Medicine. Vancomycin was purchased from Sigma. Compounds were obtained from various suppliers as listed in Table S1. Computer-aided drug design – database searching Identification of compounds similar to BAS00127538 was carried out using chemical/physiochemical similarity searches with MACCS17 and MPMFP18 fingerprints using the program MOE (Chemical Computing Group Inc.).19 The query compound, Figure 1, was chosen to account for interactions of the positively charged oxygen of BAS00127538 with the phosphate of Lipid II as indicated by molecular dynamics (MD) simulations and nuclear magnetic resonance data as discussed in our previous study. An in-house database in the University of Maryland Computer-Aided Drug Design (CADD) Center with 5.04 million compounds was used for the similarity searching. Similar compounds with a Tanimoto index over a selected cutoff value and with drug-like characteristics that maximize bioavailability20 w (...truncated)