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Polymyxin Binding to the Bacterial Outer Membrane Reveals Cation Displacement and Increasing Membrane Curvature in Susceptible but Not in Resistant Lipopolysaccharide Chemotypes
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Univ Fed Pernambuco, Dept Fundamental Chem, BR-50740560 Recife, PE, Brazil.
2017 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 57, no 9, p. 2181-2193Article in journal (Refereed) Published
Abstract [en]

Lipid-A is the causative agent of Gram-negative sepsis and is responsible for an increasingly high mortality rate among hospitalized patients. Compounds that bind Lipid-A can limit this inflammatory process. The cationic antimicrobial peptide polymyxin B (Pmx-B) is one of the simplest molecules capable of selectively binding to Lipid-A and may serve as a model for further development of Lipid-A binding agents. Gram-negative bacteria resistance to Pmx-B relies on the upregulation of a number of regulatory systems, which promote chemical modifications of the lipopolysaccharide (LPS) structure and leads to major changes in the physical chemical properties of the outer membrane. A detailed understanding of how the chemical structure of the LPS modulates macroscopic properties of the outer membrane is paramount for the design and optimization of novel drugs targeting clinically relevant strains. We have performed a systematic investigation of Pmx-B binding to outer membrane models composed of distinct LPS chemotypes experimentally shown to be either resistant or susceptible to the peptide. Molecular dynamics simulations were carried out for Pmx-B bound to the penta- and hexa-acylated forms of Lipid-A (more susceptible) and Lipid-A modified with 4-amino-4-deoxy-L-arabinose (resistant) as well as the penta-acylated form of LPS Re (less susceptible). The present simulations show that upon binding to the bacterial outer membrane surface, Pmx-B promotes cation displacement and structural changes in membrane curvature and integrity as a function of the LPS chemotype susceptibility or resistance to the antimicrobial peptide.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC , 2017. Vol. 57, no 9, p. 2181-2193
National Category
Biophysics Pharmaceutical Sciences Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-140919DOI: 10.1021/acs.jcim.7b00271ISI: 000411914200009PubMedID: 28805387OAI: oai:DiVA.org:umu-140919DiVA, id: diva2:1153739
Available from: 2017-10-31 Created: 2017-10-31 Last updated: 2018-06-09Bibliographically approved

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Soares, Thereza A.

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