Investigating the interaction of octapeptin A3 with model bacterial membranes

Han, Mei-Ling, Shen, Hsin-Hui, Hansford, Karl A., Schneider, Elena K., Sivanesan, Sivashangarie, Roberts, Kade D., Thompson, Philip E., Le Brun, Anton P., Zhu, Yan, Sani, Marc-Antoine, Separovic, Frances, Blaskovich, Mark A. T., Baker, Mark A., Moskowitz, Samuel M., Cooper, Matthew A., Li, Jian and Velkov, Tony (2017) Investigating the interaction of octapeptin A3 with model bacterial membranes. ACS Infectious Diseases, 3 8: 606-619. doi:10.1021/acsinfecdis.7b00065


Author Han, Mei-Ling
Shen, Hsin-Hui
Hansford, Karl A.
Schneider, Elena K.
Sivanesan, Sivashangarie
Roberts, Kade D.
Thompson, Philip E.
Le Brun, Anton P.
Zhu, Yan
Sani, Marc-Antoine
Separovic, Frances
Blaskovich, Mark A. T.
Baker, Mark A.
Moskowitz, Samuel M.
Cooper, Matthew A.
Li, Jian
Velkov, Tony
Title Investigating the interaction of octapeptin A3 with model bacterial membranes
Journal name ACS Infectious Diseases   Check publisher's open access policy
ISSN 2373-8227
Publication date 2017-08-11
Year available 2017
Sub-type Article (original research)
DOI 10.1021/acsinfecdis.7b00065
Open Access Status Not yet assessed
Volume 3
Issue 8
Start page 606
End page 619
Total pages 14
Place of publication Washington, DC United States
Publisher American Chemical Society
Language eng
Subject 2725 Infectious Diseases
Abstract Octapeptins are cyclic lipopeptides with a broader spectrum of activity against fungi and polymyxin-resistant Gram-negative and Gram-positive bacteria. In the present study, we investigated the interaction of octapeptin A3 with asymmetric outer membrane models of Gram-negative pathogen Pseudomonas aeruginosa using neutron reflectometry, together with fluorimetric and calorimetry methods. For the first time, our neutron reflectometry results reveal that the interaction of octapeptin A3 with the Gram-negative outer membrane involves an initial transient polar interaction with the phospholipid and lipid A headgroups, followed by the penetration of the entire octapeptin molecule into the fatty acyl core of the outer membrane. This mechanism contrasts with that of polymyxin B, which specifically targets lipid A, whereas octapeptins appear to target both lipid A and phospholipids. Furthermore, the mechanism of octapeptins does not appear to be highly dependent on an initial complementary electrostatic interaction with lipid A, which accounts for their ability to bind to lipid A of polymyxin-resistant Gram-negative bacteria that is modified with cationic moieties that act to electrostatically repel the cationic polymyxin molecule. The presented findings shed new light on the mechanism whereby octapeptins penetrate the outer membrane of polymyxin-resistant Gram-negative pathogens and highlight their potential as candidates for development as new antibiotics against problematic multi-drug-resistant pathogens.
Formatted abstract
Octapeptins are cyclic lipopeptides with a broader spectrum of activity against fungi and polymyxin-resistant Gram-negative and Gram-positive bacteria. In the present study, we investigated the interaction of octapeptin A3 with asymmetric outer membrane models of Gram-negative pathogen Pseudomonas aeruginosa using neutron reflectometry, together with fluorimetric and calorimetry methods. For the first time, our neutron reflectometry results reveal that the interaction of octapeptin A3 with the Gram-negative outer membrane involves an initial transient polar interaction with the phospholipid and lipid A headgroups, followed by the penetration of the entire octapeptin molecule into the fatty acyl core of the outer membrane. This mechanism contrasts with that of polymyxin B, which specifically targets lipid A, whereas octapeptins appear to target both lipid A and phospholipids. Furthermore, the mechanism of octapeptins does not appear to be highly dependent on an initial complementary electrostatic interaction with lipid A, which accounts for their ability to bind to lipid A of polymyxin-resistant Gram-negative bacteria that is modified with cationic moieties that act to electrostatically repel the cationic polymyxin molecule. The presented findings shed new light on the mechanism whereby octapeptins penetrate the outer membrane of polymyxin-resistant Gram-negative pathogens and highlight their potential as candidates for development as new antibiotics against problematic multi-drug-resistant pathogens.
Keyword Mode of action
Multidrug resistance
Octapeptin
Polymyxin
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID R01A1070896
R21AI098731/R33AI098731
APP1005350
P4787
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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Created: Mon, 04 Sep 2017, 01:00:49 EST by Web Cron on behalf of Institute for Molecular Bioscience