Salmonella enterica serovar Typhimurium waaP mutants show increased susceptibility to polymyxin and loss of virulence in vivo

被引:78
作者
Yethon, JA
Gunn, JS
Ernst, RK
Miller, SI
Laroche, L
Malo, D
Whitfield, C [1 ]
机构
[1] Univ Guelph, Dept Microbiol, Guelph, ON N1G 2W1, Canada
[2] Univ Guelph, Canadian Bacterial Dis Network, Guelph, ON N1G 2W1, Canada
[3] McGill Univ, Ctr Study Host Resistance, Montreal, PQ H3G 1A4, Canada
[4] Univ Texas, Hlth Sci Ctr, Dept Microbiol, San Antonio, TX 78284 USA
[5] Univ Washington, Dept Med, Seattle, WA 98195 USA
[6] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA
关键词
D O I
10.1128/IAI.68.8.4485-4491.2000
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
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收藏
页码:4485 / 4491
页数:7
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