A Klebsiella pneumoniae antibiotic resistance mechanism that subdues host defences and promotes virulence

Kidd, Timothy J., Mills, Grant, Sá-Pessoa, Joana, Dumigan, Amy , Frank, Christian G., Insua, José L., Ingram, Rebecca, Hobley, Laura and Bengoechea, José A. (2017) A Klebsiella pneumoniae antibiotic resistance mechanism that subdues host defences and promotes virulence. EMBO Molecular Medicine, 9 4: 430-447. doi:10.15252/emmm.201607336


Author Kidd, Timothy J.
Mills, Grant
Sá-Pessoa, Joana
Dumigan, Amy
Frank, Christian G.
Insua, José L.
Ingram, Rebecca
Hobley, Laura
Bengoechea, José A.
Title A Klebsiella pneumoniae antibiotic resistance mechanism that subdues host defences and promotes virulence
Formatted title
A Klebsiella pneumoniae antibiotic resistance mechanism that subdues host defences and promotes virulence
Journal name EMBO Molecular Medicine   Check publisher's open access policy
ISSN 1757-4684
1757-4676
Publication date 2017-02-15
Year available 2017
Sub-type Article (original research)
DOI 10.15252/emmm.201607336
Open Access Status DOI
Volume 9
Issue 4
Start page 430
End page 447
Total pages 18
Place of publication Weinheim, Germany
Publisher Wiley - V C H Verlag GmbH & Co. KGaA
Language eng
Subject 1313 Molecular Medicine
Abstract Klebsiella pneumoniae is an important cause of multidrug-resistant infections worldwide. Recent studies highlight the emergence of multidrug-resistant K. pneumoniae strains which show resistance to colistin, a last-line antibiotic, arising from mutational inactivation of the mgrB regulatory gene. However, the precise molecular resistance mechanisms of mgrB-associated colistin resistance and its impact on virulence remain unclear. Here, we constructed an mgrB gene K. pneumoniae mutant and performed characterisation of its lipid A structure, polymyxin and antimicrobial peptide resistance, virulence and inflammatory responses upon infection. Our data reveal that mgrB mutation induces PhoPQ-governed lipid A remodelling which confers not only resistance to polymyxins, but also enhances K. pneumoniae virulence by decreasing antimicrobial peptide susceptibility and attenuating early host defence response activation. Overall, our findings have important implications for patient management and antimicrobial stewardship, while also stressing antibiotic resistance development is not inexorably linked with subdued bacterial fitness and virulence.
Formatted abstract
Klebsiella pneumoniae is an important cause of multidrug‐resistant infections worldwide. Recent studies highlight the emergence of multidrug‐resistant K. pneumoniae strains which show resistance to colistin, a last‐line antibiotic, arising from mutational inactivation of the mgrB regulatory gene. However, the precise molecular resistance mechanisms of mgrB‐associated colistin resistance and its impact on virulence remain unclear. Here, we constructed an mgrB gene K. pneumoniae mutant and performed characterisation of its lipid A structure, polymyxin and antimicrobial peptide resistance, virulence and inflammatory responses upon infection. Our data reveal that mgrB mutation induces PhoPQ‐governed lipid A remodelling which confers not only resistance to polymyxins, but also enhances K. pneumoniae virulence by decreasing antimicrobial peptide susceptibility and attenuating early host defence response activation. Overall, our findings have important implications for patient management and antimicrobial stewardship, while also stressing antibiotic resistance development is not inexorably linked with subdued bacterial fitness and virulence.
Keyword Antimicrobial peptides
Klebsiella pneumoniae
MgrB
Polymyxins
Virulence
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 4571-2013
GNT1088448
600368
PCIG13-GA-2013-618162
BB/L007223/1
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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Created: Fri, 17 Feb 2017, 11:09:51 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences