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Journal of Bacteriology, August 2005, p. 5387-5396, Vol. 187, No. 15
0021-9193/05/$08.00+0     doi:10.1128/JB.187.15.5387-5396.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Cationic Antimicrobial Peptide Resistance in Neisseria meningitidis

Yih-Ling Tzeng,¹ Karita D. Ambrose,^2, Susu Zughaier,¹ Xiaoliu Zhou,¹ Yoon K. Miller,¹ William M. Shafer,^2,3 and David S. Stephens^1,2,3*

Division of Infectious Diseases, Department of Medicine,¹ Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta,² Laboratories of Bacterial Pathogenesis, Department of Veterans Affairs Medical Center, Decatur, Georgia³

Received 3 January 2005/ Accepted 4 May 2005

Cationic antimicrobial peptides (CAMPs) are important components of the innate host defense system against microbial infections and microbial products. However, the human pathogen Neisseria meningitidis is intrinsically highly resistant to CAMPs, such as polymyxin B (PxB) (MIC 512 µg/ml). To ascertain the mechanisms by which meningococci resist PxB, mutants that displayed increased sensitivity (4-fold) to PxB were identified from a library of mariner transposon mutants generated in a meningococcal strain, NMB. Surprisingly, more than half of the initial PxB-sensitive mutants had insertions within the mtrCDE operon, which encodes proteins forming a multidrug efflux pump. Additional PxB-sensitive mariner mutants were identified from a second round of transposon mutagenesis performed in an mtr efflux pump-deficient background. Further, a mutation in lptA, the phosphoethanolamine (PEA) transferase responsible for modification of the lipid A head groups, was identified to cause the highest sensitivity to PxB. Mutations within the mtrD or lptA genes also increased meningococcal susceptibility to two structurally unrelated CAMPs, human LL-37 and protegrin-1. Consistently, PxB neutralized inflammatory responses elicited by the lptA mutant lipooligosaccharide more efficiently than those induced by wild-type lipooligosaccharide. mariner mutants with increased resistance to PxB were also identified in NMB background and found to contain insertions within the pilMNOPQ operon involved in pilin biogenesis. Taken together, these data indicated that meningococci utilize multiple mechanisms including the action of the MtrC-MtrD-MtrE efflux pump and lipid A modification as well as the type IV pilin secretion system to modulate levels of CAMP resistance. The modification of meningococcal lipid A head groups with PEA also prevents neutralization of the biological effects of endotoxin by CAMP.

Present address: Wyeth, Pearl River, N.Y.

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