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Elucidation of the RamA Regulon in Klebsiella pneumoniae Reveals a Role in LPS Regulation

De Majumdar, Shyamasree, Yu, Jing, Fookes, Maria, McAteer, Sean P., Llobet, Enrique, Finn, Sarah, Spence, Shaun, Monaghan, Avril, Kissenpfennig, Adrien, Ingram, Rebecca J., Bengoechea, José, Gally, David L., Fanning, Séamus, Elborn, Joseph S., Schneiders, Thamarai and Hauser, Alan (2015) Elucidation of the RamA Regulon in Klebsiella pneumoniae Reveals a Role in LPS Regulation. PLOS Pathogens, 11 (1). e1004627. [Journal article]

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URL: http://dx.doi.org/10.1371/journal.ppat.1004627

DOI: 10.1371/journal.ppat.1004627


Klebsiella pneumoniae is a significant human pathogen, in part due to high rates of multidrug resistance. RamA is an intrinsic regulator in K. pneumoniae established to be important for the bacterial response to antimicrobial challenge; however, little is known about its possible wider regulatory role in this organism during infection. In this work, we demonstrate that RamA is a global transcriptional regulator that significantly perturbs the transcriptional landscape of K. pneumoniae, resulting in altered microbe-drug or microbe-host response. This is largely due to the direct regulation of 68 genes associated with a myriad of cellular functions. Importantly, RamA directly binds and activates the lpxC, lpxL-2 and lpxO genes associated with lipid A biosynthesis, thus resulting in modifications within the lipid A moiety of the lipopolysaccharide. RamA-mediated alterations decrease susceptibility to colistin E, polymyxin B and human cationic antimicrobial peptide LL-37. Increased RamA levels reduce K. pneumoniae adhesion and uptake into macrophages, which is supported by in vivo infection studies, that demonstrate increased systemic dissemination of ramA overexpressing K. pneumoniae. These data establish that RamA-mediated regulation directly perturbs microbial surface properties, including lipid A biosynthesis, which facilitate evasion from the innate host response. This highlights RamA as a global regulator that confers pathoadaptive phenotypes with implications for our understanding of the pathogenesis of Enterobacter, Salmonella and Citrobacter spp. that express orthologous RamA proteins.

Item Type:Journal article
Keywords:RamA, Klebsiella
Faculties and Schools:Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute > Genomic Medicine
Biomedical Sciences Research Institute
ID Code:38120
Deposited By: Dr Shyamasree De Majumdar
Deposited On:13 Jun 2017 09:26
Last Modified:13 Jun 2017 09:26

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