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Infection and Immunity, August 2000, p. 4485-4491, Vol. 68, No. 8
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Salmonella enterica Serovar Typhimurium waaP Mutants Show Increased Susceptibility to Polymyxin and Loss of Virulence In Vivo

Jeremy A. Yethon,1,2 John S. Gunn,3 Robert K. Ernst,4 Samuel I. Miller,4 Line Laroche,5 Danielle Malo,1,5 and Chris Whitfield1,2,*

Canadian Bacterial Diseases Network,1 Department of Microbiology, University of Guelph, Guelph, Ontario N1G 2W1,2 and Centre for the Study of Host Resistance, McGill University, Montreal, Quebec H3G 1A4,5 Canada; Department of Microbiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284-77583; and Departments of Medicine and Microbiology, University of Washington, Seattle, Washington 981954

Received 14 December 1999/Returned for modification 28 February 2000/Accepted 26 April 2000

In Escherichia coli, the waaP (rfaP) gene product was recently shown to be responsible for phosphorylation of the first heptose residue of the lipopolysaccharide (LPS) inner core region. WaaP was also shown to be necessary for the formation of a stable outer membrane. These earlier studies were performed with an avirulent rough strain of E. coli (to facilitate the structural chemistry required to properly define waaP function); therefore, we undertook the creation of a waaP mutant of Salmonella enterica serovar Typhimurium to assess the contribution of WaaP and LPS core phosphorylation to the biology of an intracellular pathogen. The S. enterica waaP mutant described here is the first to be both genetically and structurally characterized, and its creation refutes an earlier claim that waaP mutations in S. enterica must be leaky to maintain viability. The mutant was shown to exhibit characteristics of the deep-rough phenotype, despite its ability to produce a full-length core capped with O antigen. Further, phosphoryl modifications in the LPS core region were shown to be required for resistance to polycationic antimicrobials. The waaP mutant was significantly more sensitive to polymyxin in both wild-type and polymyxin-resistant backgrounds, despite the decreased negative charge of the mutant LPSs. In addition, the waaP mutation was shown to cause a complete loss of virulence in mouse infection models. Taken together, these data indicate that WaaP is a potential target for the development of novel therapeutic agents.

* Corresponding author. Mailing address: Department of Microbiology, University of Guelph, Guelph, Ontario N1G 2W1, Canada. Phone: (519) 824-4120, ext. 3478. Fax: (519) 837-1802. E-mail: cwhitfie{at}uoguelph.ca.

Infection and Immunity, August 2000, p. 4485-4491, Vol. 68, No. 8
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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