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- Title
Threading the Needle: Small-Molecule Targeting of a Xenobiotic Receptor to Ablate Escherichia coli Polysaccharide Capsule Expression Without Altering Antibiotic Resistance.
- Authors
Arshad, Mehreen; Goller, Carlos C.; Pilla, Danielle; Schoenen, Frank J.; Seed, Patrick C.
- Abstract
<bold>Background: </bold>Uropathogenic Escherichia coli (UPEC), a leading cause of urinary tract and invasive infections worldwide, is rapidly acquiring multidrug resistance, hastening the need for selective new anti-infective agents. Here we demonstrate the molecular target of DU011, our previously discovered potent, nontoxic, small-molecule inhibitor of UPEC polysaccharide capsule biogenesis and virulence.<bold>Methods: </bold>Real-time polymerase chain reaction analysis and a target-overexpression drug-suppressor screen were used to localize the putative inhibitor target. A thermal shift assay quantified interactions between the target protein and the inhibitor, and a novel DNase protection assay measured chemical inhibition of protein-DNA interactions. Virulence of a regulatory target mutant was assessed in a murine sepsis model.<bold>Results: </bold>MprA, a MarR family transcriptional repressor, was identified as the putative target of the DU011 inhibitor. Thermal shift measurements indicated the formation of a stable DU011-MprA complex, and DU011 abrogated MprA binding to its DNA promoter site. Knockout of mprA had effects similar to that of DU011 treatment of wild-type bacteria: a loss of encapsulation and complete attenuation in a murine sepsis model, without any negative change in antibiotic resistance.<bold>Conclusions: </bold>MprA regulates UPEC polysaccharide encapsulation, is essential for UPEC virulence, and can be targeted without inducing antibiotic resistance.
- Subjects
SMALL molecules; ESCHERICHIA coli; URINARY tract infections; MULTIDRUG resistance; ANTI-infective agents; POLYMERASE chain reaction; ANIMAL experimentation; ANTIBIOTICS; BIOLOGICAL models; DRUG resistance in microorganisms; DRUG design; ESCHERICHIA coli diseases; GENETIC techniques; MICE; PROTEINS; RESEARCH funding; MICROBIAL virulence; BACTERIAL capsules; CHEMICAL inhibitors; PHARMACODYNAMICS
- Publication
Journal of Infectious Diseases, 2016, Vol 213, Issue 8, p1330
- ISSN
0022-1899
- Publication type
journal article
- DOI
10.1093/infdis/jiv584