title: AKlebsiella pneumoniaeantibiotic resistance mechanism that subdues host defences and promotes virulence.
abstract: Klebsiella pneumoniaeis an important cause of multidrug-resistant infections worldwide. Recent studies highlight the emergence of multidrug-resistantK. pneumoniaestrains which show resistance to colistin, a last-line antibiotic, arising from mutational inactivation of themgrBregulatory gene. However, the precise molecular resistance mechanisms ofmgrB-associated colistin resistance and its impact on virulence remain unclear. Here, we constructed anmgrBgeneK. pneumoniaemutant and performed characterisation of its lipid A structure, polymyxin and antimicrobial peptide resistance, virulence and inflammatory responses upon infection. Our data reveal thatmgrBmutation induces PhoPQ-governed lipid A remodelling which confers not only resistance to polymyxins, but also enhancesK. pneumoniaevirulence 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.
authors.affiliation: Centre for Experimental Medicine, Queen's University Belfast, Belfast, UK.|School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Qld, Australia.|Child Health Research Centre, The University of Queensland, Brisbane, Qld, Australia.
authors.forename: Timothy J
authors.identifier: 0000-0002-6135-6364
authors.initials: TJ
authors.lastname: Kidd
authors.affiliation: Centre for Experimental Medicine, Queen's University Belfast, Belfast, UK.
authors.forename: Grant
authors.initials: G
authors.lastname: Mills
authors.affiliation: Centre for Experimental Medicine, Queen's University Belfast, Belfast, UK.
authors.forename: Joana
authors.initials: J
authors.lastname: Sá-Pessoa
authors.affiliation: Centre for Experimental Medicine, Queen's University Belfast, Belfast, UK.
authors.forename: Amy
authors.initials: A
authors.lastname: Dumigan
authors.affiliation: Centre for Experimental Medicine, Queen's University Belfast, Belfast, UK.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Frank
authors.affiliation: Centre for Experimental Medicine, Queen's University Belfast, Belfast, UK.
authors.forename: José L
authors.initials: JL
authors.lastname: Insua
authors.affiliation: Centre for Experimental Medicine, Queen's University Belfast, Belfast, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ingram
authors.affiliation: Centre for Experimental Medicine, Queen's University Belfast, Belfast, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Hobley
authors.affiliation: Centre for Experimental Medicine, Queen's University Belfast, Belfast, UK j.bengoechea@qub.ac.uk.
authors.forename: José A
authors.identifier: 0000-0002-9677-8751
authors.initials: JA
authors.lastname: Bengoechea
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology; D058491:Bacterial Load; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D003091:Colistin / Q000494:pharmacology; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D006801:Humans; D007710:Klebsiella Infections / Q000382:microbiology / Q000473:pathology; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000472:pathogenicity*; D007915:Lepidoptera; D008050:Lipid A / Q000737:chemistry; D008168:Lung / Q000382:microbiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D011113:Polymyxins / Q000494:pharmacology; D016019:Survival Analysis; D014774:Virulence
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D008050:Lipid A; D008565:Membrane Proteins; D011113:Polymyxins; D003091:Colistin
keywords: 
  Klebsiella pneumoniae
  ; 
  mgrB
  ; antimicrobial peptides; polymyxins; virulence