Turning defense into offense: defensin mimetics as novel antibiotics targeting lipid II.
We have previously reported on the functional interaction of Lipid II with human alpha-defensins, a class of antimicrobial peptides. Lipid II is an essential precursor for bacterial cell wall biosynthesis and an ideal and validated target for natural antibiotic compounds. Using a combination of stru...
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2013
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oai:doaj.org-article:9a23ac4bc9d6450683ee71060a7b36542021-11-18T06:07:22ZTurning defense into offense: defensin mimetics as novel antibiotics targeting lipid II.1553-73661553-737410.1371/journal.ppat.1003732https://doaj.org/article/9a23ac4bc9d6450683ee71060a7b36542013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24244161/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374We have previously reported on the functional interaction of Lipid II with human alpha-defensins, a class of antimicrobial peptides. Lipid II is an essential precursor for bacterial cell wall biosynthesis and an ideal and validated target for natural antibiotic compounds. Using a combination of structural, functional and in silico analyses, we present here the molecular basis for defensin-Lipid II binding. Based on the complex of Lipid II with Human Neutrophil peptide-1, we could identify and characterize chemically diverse low-molecular weight compounds that mimic the interactions between HNP-1 and Lipid II. Lead compound BAS00127538 was further characterized structurally and functionally; it specifically interacts with the N-acetyl muramic acid moiety and isoprenyl tail of Lipid II, targets cell wall synthesis and was protective in an in vivo model for sepsis. For the first time, we have identified and characterized low molecular weight synthetic compounds that target Lipid II with high specificity and affinity. Optimization of these compounds may allow for their development as novel, next generation therapeutic agents for the treatment of Gram-positive pathogenic infections.Kristen M VarneyAlexandre M J J BonvinMarzena PazgierJakob MalinWenbo YuEugene AtehTaiji OashiWuyuan LuJing HuangMarlies Diepeveen-de BuinJoseph BryantEefjan BreukinkAlexander D MackerellErik P H de LeeuwPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 11, p e1003732 (2013) |
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Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
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Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Kristen M Varney Alexandre M J J Bonvin Marzena Pazgier Jakob Malin Wenbo Yu Eugene Ateh Taiji Oashi Wuyuan Lu Jing Huang Marlies Diepeveen-de Buin Joseph Bryant Eefjan Breukink Alexander D Mackerell Erik P H de Leeuw Turning defense into offense: defensin mimetics as novel antibiotics targeting lipid II. |
| description |
We have previously reported on the functional interaction of Lipid II with human alpha-defensins, a class of antimicrobial peptides. Lipid II is an essential precursor for bacterial cell wall biosynthesis and an ideal and validated target for natural antibiotic compounds. Using a combination of structural, functional and in silico analyses, we present here the molecular basis for defensin-Lipid II binding. Based on the complex of Lipid II with Human Neutrophil peptide-1, we could identify and characterize chemically diverse low-molecular weight compounds that mimic the interactions between HNP-1 and Lipid II. Lead compound BAS00127538 was further characterized structurally and functionally; it specifically interacts with the N-acetyl muramic acid moiety and isoprenyl tail of Lipid II, targets cell wall synthesis and was protective in an in vivo model for sepsis. For the first time, we have identified and characterized low molecular weight synthetic compounds that target Lipid II with high specificity and affinity. Optimization of these compounds may allow for their development as novel, next generation therapeutic agents for the treatment of Gram-positive pathogenic infections. |
| format |
article |
| author |
Kristen M Varney Alexandre M J J Bonvin Marzena Pazgier Jakob Malin Wenbo Yu Eugene Ateh Taiji Oashi Wuyuan Lu Jing Huang Marlies Diepeveen-de Buin Joseph Bryant Eefjan Breukink Alexander D Mackerell Erik P H de Leeuw |
| author_facet |
Kristen M Varney Alexandre M J J Bonvin Marzena Pazgier Jakob Malin Wenbo Yu Eugene Ateh Taiji Oashi Wuyuan Lu Jing Huang Marlies Diepeveen-de Buin Joseph Bryant Eefjan Breukink Alexander D Mackerell Erik P H de Leeuw |
| author_sort |
Kristen M Varney |
| title |
Turning defense into offense: defensin mimetics as novel antibiotics targeting lipid II. |
| title_short |
Turning defense into offense: defensin mimetics as novel antibiotics targeting lipid II. |
| title_full |
Turning defense into offense: defensin mimetics as novel antibiotics targeting lipid II. |
| title_fullStr |
Turning defense into offense: defensin mimetics as novel antibiotics targeting lipid II. |
| title_full_unstemmed |
Turning defense into offense: defensin mimetics as novel antibiotics targeting lipid II. |
| title_sort |
turning defense into offense: defensin mimetics as novel antibiotics targeting lipid ii. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/9a23ac4bc9d6450683ee71060a7b3654 |
| work_keys_str_mv |
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| _version_ |
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