Investigating the Interaction of Octapeptin A3 with Model Bacterial Membranes

Mei Ling Han, Hsin Hui Shen, Karl A. Hansford, Elena K. Schneider, Sivashangarie Sivanesan, Kade D. Roberts, Philip E. Thompson, Anton P Le Brun, Yan Zhu, Marc-Antoine Sani, Frances Separovic, Mark A T Blaskovich, Mark A. Baker, Samuel M. Moskowitz, Matthew A Cooper, Jian Li, Tony Velkov

Research output: Contribution to journalArticleResearchpeer-review

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)606-619
Number of pages14
JournalACS Infectious Diseases
Volume3
Issue number8
DOIs
Publication statusPublished - 11 Aug 2017

Keywords

  • mode of action
  • multidrug resistance
  • octapeptin
  • polymyxin

Cite this

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. / Investigating the Interaction of Octapeptin A3 with Model Bacterial Membranes. In: ACS Infectious Diseases. 2017 ; Vol. 3, No. 8. pp. 606-619.
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title = "Investigating the Interaction of Octapeptin A3 with Model Bacterial Membranes",
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.",
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author = "Han, {Mei Ling} and Shen, {Hsin Hui} and Hansford, {Karl A.} and Schneider, {Elena K.} and Sivashangarie Sivanesan and Roberts, {Kade D.} and Thompson, {Philip E.} and {Le Brun}, {Anton P} and Yan Zhu and Marc-Antoine Sani and Frances Separovic and Blaskovich, {Mark A T} and Baker, {Mark A.} and Moskowitz, {Samuel M.} and Cooper, {Matthew A} and Jian Li and Tony Velkov",
year = "2017",
month = "8",
day = "11",
doi = "10.1021/acsinfecdis.7b00065",
language = "English",
volume = "3",
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Han, ML, Shen, HH, Hansford, KA, Schneider, EK, Sivanesan, S, Roberts, KD, Thompson, PE, Le Brun, AP, Zhu, Y, Sani, M-A, Separovic, F, Blaskovich, MAT, Baker, MA, Moskowitz, SM, Cooper, MA, Li, J & Velkov, T 2017, 'Investigating the Interaction of Octapeptin A3 with Model Bacterial Membranes', ACS Infectious Diseases, vol. 3, no. 8, pp. 606-619. https://doi.org/10.1021/acsinfecdis.7b00065

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; Velkov, Tony.

In: ACS Infectious Diseases, Vol. 3, No. 8, 11.08.2017, p. 606-619.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Investigating the Interaction of Octapeptin A3 with Model Bacterial Membranes

AU - Han, Mei Ling

AU - Shen, Hsin Hui

AU - Hansford, Karl A.

AU - Schneider, Elena K.

AU - Sivanesan, Sivashangarie

AU - Roberts, Kade D.

AU - Thompson, Philip E.

AU - Le Brun, Anton P

AU - Zhu, Yan

AU - Sani, Marc-Antoine

AU - Separovic, Frances

AU - Blaskovich, Mark A T

AU - Baker, Mark A.

AU - Moskowitz, Samuel M.

AU - Cooper, Matthew A

AU - Li, Jian

AU - Velkov, Tony

PY - 2017/8/11

Y1 - 2017/8/11

N2 - 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.

AB - 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.

KW - mode of action

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KW - octapeptin

KW - polymyxin

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