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J. Biol. Chem., Vol. 282, Issue 21, 15569-15577, May 25, 2007

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Secondary Acylation of Klebsiella pneumoniae Lipopolysaccharide Contributes to Sensitivity to Antibacterial Peptides^*

Abigail Clements¹, Dedreia Tull^¶, Adam W. Jenney, Jacinta L. Farn, Sang-Hyun Kim^||, Russell E. Bishop^||, Joseph B. McPhee^**, Robert E. W. Hancock^**, Elizabeth L. Hartland, Martin J. Pearse, Odilia L. C. Wijburg², David C. Jackson, Malcolm J. McConville^¶34, and Richard A. Strugnell⁴⁵

From the CRC for Vaccine Technology in the Department of Microbiology & Immunology and the ^¶Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3010, Australia, CSL Ltd. Parkville, Victoria 3052, Australia, the ^||Department of Biochemistry, University of Toronto, Ontario M5S1A8, Canada, the ^**Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T1Z4, Canada, the CRC for Vaccine Technology in the Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia, and the Australian Bacterial Pathogenesis Program in the Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia

Klebsiella pneumoniae is an important cause of nosocomial Gram-negative sepsis. Lipopolysaccharide (LPS) is considered to be a major virulence determinant of this encapsulated bacterium and most mutations to the lipid A anchor of LPS are conditionally lethal to the bacterium. We studied the role of LPS acylation in K. pneumoniae disease pathogenesis by using a mutation of lpxM (msbB/waaN), which encodes the enzyme responsible for late secondary acylation of immature lipid A molecules. A K. pneumoniae B5055 (K2:O1) lpxM mutant was found to be attenuated for growth in the lungs in a mouse pneumonia model leading to reduced lethality of the bacterium. B5055lpxM exhibited similar sensitivity to phagocytosis or complement-mediated lysis than B5055, unlike the non-encapsulated mutant B5055nm. In vitro, B5055lpxM showed increased permeability of the outer membrane and an increased susceptibility to certain antibacterial peptides suggesting that in vivo attenuation may be due in part to sensitivity to antibacterial peptides present in the lungs of BALB/c mice. These data support the view that lipopolysaccharide acylation plays a important role in providing Gram-negative bacteria some resistance to structural and innate defenses and especially the antibacterial properties of detergents (e.g. bile) and cationic defensins.

Received for publication, February 20, 2007

^* This research was supported in part by the National Health and Medical Research Council (NH&MRC) of Australia and the Cooperative Research Centre for Vaccine Technology. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ A NH&MRC Dora Lush Scholar.

² A NH&MRC RD Wright Fellow.

³ A NH&MRC Principal Research Fellow.

⁴ Both authors made equal contributions as senior authors.

⁵ To whom correspondence should be addressed: Dept. of Microbiology & Immunology, University of Melbourne, Parkville VIC 3010, Australia. Tel.: 61-3-8344-5712; Fax: 61-3-9347-1540; E-mail: rastru{at}unimelb.edu.au.

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