Molecular basis for the increased polymyxin susceptibility of Klebsiella pneumoniae strains with under-acylated lipid A

Velkov, Tony, Soon, Rachel L., Chong, Pei L., Huang, Johnny X., Cooper, Matthew A., Azad, Mohammad A. K., Baker, Mark A., Thompson, Philip E., Roberts, Kade, Nation, Roger L., Clements, Abigail, Strugnell, Richard A. and Li, Jian (2013) Molecular basis for the increased polymyxin susceptibility of Klebsiella pneumoniae strains with under-acylated lipid A. Innate Immunity, 19 3: 265-277. doi:10.1177/1753425912459092

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Author Velkov, Tony
Soon, Rachel L.
Chong, Pei L.
Huang, Johnny X.
Cooper, Matthew A.
Azad, Mohammad A. K.
Baker, Mark A.
Thompson, Philip E.
Roberts, Kade
Nation, Roger L.
Clements, Abigail
Strugnell, Richard A.
Li, Jian
Title Molecular basis for the increased polymyxin susceptibility of Klebsiella pneumoniae strains with under-acylated lipid A
Formatted title
Molecular basis for the increased polymyxin susceptibility of Klebsiella pneumoniae strains with under-acylated lipid A
Journal name Innate Immunity   Check publisher's open access policy
ISSN 1753-4259
1753-4267
Publication date 2013-06-01
Year available 2013
Sub-type Article (original research)
DOI 10.1177/1753425912459092
Open Access Status Not yet assessed
Volume 19
Issue 3
Start page 265
End page 277
Total pages 13
Place of publication London, United Kingdom
Publisher Sage
Language eng
Subject 2404 Microbiology
2403 Immunology
1312 Molecular Biology
1307 Cell Biology
2725 Infectious Diseases
Abstract The impact of under-acylation of lipid A on the interaction between Klebsiella pneumoniae LPS and polymyxins B and E was examined with fluorometric and calorimetric methods, and by 1H NMR, using a paired wild type (WT) and the ΔlpxM mutant strains B5055 and B5055ΔlpxM, which predominantly express LPS with hexa- and penta-acylated lipid A structures respectively. LPS from B5055ΔlpxM displayed a fourfold increased binding affinity for polymyxins B and E compared with the B5055 WT LPS. EC50 values were consistent with polymyxin minimum inhibitory concentration (MIC) values for each strain. Accordingly, polymyxin exposure considerably enhanced the permeability of the B5055ΔlpxM OM. Analysis of the melting profiles of isolated LPS aggregates suggested that bactericidal polymyxin activity may relate to the acyl chains' phase of the outer membrane (OM). The enhanced polymyxin susceptibility of B5055ΔlpxM may be attributable to the favorable insertion of polymyxins into the more fluid OM compared with B5055. Molecular models of the polymyxin B-lipid A complex illuminate the key role of the lipid A acyl chains for complexation of polymyxin. The data provide important insight into the molecular basis for the increased polymyxin susceptibility of K. pneumoniae strains with under-acylated lipid A. Under-acylation appears to facilitate the integration of the N-terminal fatty-acyl chain of polymyxin into the OM resulting in an increased susceptibility to its antimicrobial activity/activities.
Formatted abstract
The impact of under-acylation of lipid A on the interaction between Klebsiella pneumoniae LPS and polymyxins B and E was examined with fluorometric and calorimetric methods, and by 1H NMR, using a paired wild type (WT) and the ΔlpxM mutant strains B5055 and B5055ΔlpxM, which predominantly express LPS with hexa- and penta-acylated lipid A structures respectively. LPS from B5055ΔlpxM displayed a fourfold increased binding affinity for polymyxins B and E compared with the B5055 WT LPS. EC50 values were consistent with polymyxin minimum inhibitory concentration (MIC) values for each strain. Accordingly, polymyxin exposure considerably enhanced the permeability of the B5055ΔlpxM OM. Analysis of the melting profiles of isolated LPS aggregates suggested that bactericidal polymyxin activity may relate to the acyl chains' phase of the outer membrane (OM). The enhanced polymyxin susceptibility of B5055ΔlpxM may be attributable to the favorable insertion of polymyxins into the more fluid OM compared with B5055. Molecular models of the polymyxin B-lipid A complex illuminate the key role of the lipid A acyl chains for complexation of polymyxin. The data provide important insight into the molecular basis for the increased polymyxin susceptibility of K. pneumoniae strains with under-acylated lipid A. Under-acylation appears to facilitate the integration of the N-terminal fatty-acyl chain of polymyxin into the OM resulting in an increased susceptibility to its antimicrobial activity/activities.
Keyword Polymyxin
Klebsiella pneumoniae
Lipopolysaccharide
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID R01A1070896
AF511105
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
Institute for Molecular Bioscience - Publications
 
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