Journal Article

Selective depletion of uropathogenic E. coli from the gut by a FimH antagonist

Spaulding, Caitlin N., Klein, Roger D., Cusumano, Zachary T., Schreiber, Henry L., Dodson, Karen W., Kau, Andrew L., Pinkner, Jerome S., Hultgren, Scott J., Remaut, Han, Janetka, James W., Ruer, Ségolène, Fremont, Daved H., Gordon, Jeffrey I.

2017

Overview

Both F17-like and type 1 pili promote intestinal colonization in mouse colonic crypts, and the high-affinity mannoside M4284 reduces intestinal colonization of uropathogenic Escherichia coli while simultaneously treating urinary tract infections without disrupting the composition of the gut microbiota. UTI reduction by mannoside Uropathogenic E. coli (UPEC) are responsible for 80% of community-acquired and 65% of nosocomial urinary tract infections (UTI), which together affect 150 million people annually. UPEC establishes reservoirs in the gut, but the factors involved in this process have remained unknown. Here, Scott Hultgren and colleagues show that both F17-like and type 1 pili promote intestinal colonization and bind to distinct glycans on epithelial cells distributed along colonic crypts. Using the high-affinity mannose analogue, mannoside M4284, which inhibits the adhesive function of type 1 pili, the authors demonstrate that it effectively reduces intestinal colonization of UPEC, while simultaneously treating UTI without significantly disrupting the composition of the gut microbiota. The authors suggest that this selective depletion of intestinal UPEC by mannosides could be used to reduce the occurrence of UTIs. Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) affect 150 million people annually 1 , 2 . Despite effective antibiotic therapy, 30–50% of patients experience recurrent UTIs 1 . In addition, the growing prevalence of UPEC that are resistant to last-line antibiotic treatments, and more recently to carbapenems and colistin, make UTI a prime example of the antibiotic-resistance crisis and emphasize the need for new approaches to treat and prevent bacterial infections 3 , 4 , 5 . UPEC strains establish reservoirs in the gut from which they are shed in the faeces, and can colonize the periurethral area or vagina and subsequently ascend through the urethra to the urinary tract, where they cause UTIs 6 . UPEC isolates encode up to 16 distinct chaperone-usher pathway pili, and each pilus type may enable colonization of a habitat in the host or environment 7 . For example, the type 1 pilus adhesin FimH binds mannose on the bladder surface, and mediates colonization of the bladder. However, little is known about the mechanisms underlying UPEC persistence in the gut 5 . Here, using a mouse model, we show that F17-like and type 1 pili promote intestinal colonization and show distinct binding to epithelial cells distributed along colonic crypts. Phylogenomic and structural analyses reveal that F17-like pili are closely related to pilus types carried by intestinal pathogens, but are restricted to extra-intestinal pathogenic E. coli . Moreover, we show that targeting FimH with M4284, a high-affinity inhibitory mannoside, reduces intestinal colonization of genetically diverse UPEC isolates, while simultaneously treating UTI, without notably disrupting the structural configuration of the gut microbiota. By selectively depleting intestinal UPEC reservoirs, mannosides could markedly reduce the rate of UTIs and recurrent UTIs.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 14/105 / 14/19 / 38/23 / 42/70 / 45/22 / 49/1 / 631/154/555 / 631/326/2565/2134 / 631/326/325/1506 / 631/326/421 / 64/60 / 82/51 / 82/83 / Adhesins, Escherichia coli - metabolism / Amino Acid Sequence / Animals / Antagonists (Biochemistry) / Control / Epithelial Cells - drug effects / Epithelial Cells - microbiology / Escherichia coli / Feces - microbiology / Female / Fimbriae Proteins - antagonists & inhibitors / Fimbriae Proteins - metabolism / Fimbriae, Bacterial - classification / Fimbriae, Bacterial - drug effects / Fimbriae, Bacterial - genetics / Fimbriae, Bacterial - metabolism / Health aspects / Humanities and Social Sciences / Humans / Intestines / Intestines - cytology / Intestines - drug effects / Intestines - microbiology / letter / Mannosides - pharmacology / Mannosides - therapeutic use / Mice / Models, Molecular / multidisciplinary / Phthalic Acids - pharmacology / Phthalic Acids - therapeutic use / Physiological aspects / Science / Urinary Bladder - drug effects / Urinary Bladder - microbiology / Urinary Tract Infections - drug therapy / Urinary Tract Infections - microbiology / Urinary Tract Infections - prevention & control / Uropathogenic Escherichia coli - classification / Uropathogenic Escherichia coli - drug effects / Uropathogenic Escherichia coli - genetics / Uropathogenic Escherichia coli - isolation & purification