Anti-Virulence FimH Inhibitors for the Treatment and Prevention of UTIs

Overmillion women suffer from urinary tract infectionsUTIannually in the U Sandof these patients will suffer from recurrent infectionsincluding approximatelypatientsmostly womenwho will suffer from highly recurrentgreater thanepisodes per yearUTIAntimicrobial treatment of UTIs has resulted in increasing antimicrobial resistance among uropathogenic EcoliUPECto first line empiric therapiessuch as trimethoprim sulfamethoxazoleand even to broad spectrum fluoroquinolonesThose with frequent recurrent UTI must often resort to long term prophylactic antimicrobial therapywhich in turn selects for more resistanceAlternative treatment options are desperately neededOver the past two decadeselucidation of bacterial pathogenic pathways in UPEC has revealed that the mannose binding tip adhesin protein of typepiliFimHis an essential virulence factorand thus a novel therapeutic target for the prevention and treatment of UTIWith this knowledgeinvestigators have identified and developedDmannose derivativescalledmannosidesas FimH antagonists that are efficacious in blocking FimH functionincluding the abilities of FimH to mediate biofilm formation and UPEC adherence to mannosylated receptors on bladder epithelial cellsUsing an interdisciplinary approach that blends medicinal chemistrymicrobiologyand pharmacologymuch progress has been made to optimize these potentorally available mannosides that attenuate acute virulenceand treat existing infections in established murine models of UTIImportantlymannosides are effective at treating antimicrobial resistant clinical strainsincluding an STESBLSuperbugstrainin vivoMannosides can even potentiate therapy with an antimicrobial that UPEC are otherwise clinically resistant toby preventing bacterial invasion into host tissuethereby exposing UPEC to host immune responses and high levels of first line antimicrobials that concentrate in the urineThis proposal is focused on continuing the lead optimization of mannosides from the Phase I SBIR project to identify a clinical candidate drug for human clinical trials of UTI therapyDevelopment efforts will focus on the optimization of Clinked mannosides and O mannoside pro drugs with improved drug like propertiesincluding increased metabolic stability and bioavailabilityIn vitro biological assays will be used to screen our lead candidates for potencyThe in vivo pharmacokineticsPKand efficacy of our best lead mannoside FimH antagonists will then be evaluated in miceOur models are relevant to human UTIand allow evaluation of mannosides for prevention and treatment of acuterecurrent and chronic UTITogether with separatebut complementarypreclinical studies funded by our industry partnerour proposed experiments will allow us to identify a clinical candidate mannoside drug to move forward to investigational new drugINDstatusThe ultimate goal of this project is to deliver a first in class anti virulence FimH mannoside antagonist drug into human clinical trialsas a new oral antimicrobial sparing therapeutic for millions of women suffering from UTIs