MICROBIOTIX, INC. — Department of Health and Human Services SBIR Phase I: NIAID

Description

Project SummaryThe CDC lists MDR Neisseria gonorrhoeaeNgas one of the three most urgent antibiotic resistance threats in the United StatesA Gram negative fastidious organismNg causes gonorrheathe second most prevalent sexually transmitted bacterial infectionSTIwith andgtestimated cases in the United States annuallyLeft untreatedgonorrhea can cause pelvic inflammatory disease in womenleading to fallopian tube scarring and infertility or may disseminatecausing joint and skin manifestationsOnce easily treatableNg has evolved resistance to nearly every antibiotic used to treat itleaving a combination of azithromycinAZMand ceftriaxoneCTXas the only currently available treatment optionImportantlya cluster of cases was recently reported in Hawaii that was resistant to both AZM and CTXhighlighting the critical need for new therapeutics targeting antibiotic resistant Ng infectionsBacterial translation is plagued by transcription errorsmRNA damageand translational frameshiftswhich can result in loss of the stop codon and non stop ribosome complex formationpreventing the release of protein products and inhibiting further translationRecovery of non stop ribosome complexes is an essential process in bacteria mediated by trans translation machinery found in every bacterial genome sequenced todateMutations in trans translation components affect viability or virulence in a wide variety of bacteria including NgIn preliminary studieswe demonstrated that tetrazole based compounds inhibit trans translationacting as potent antimicrobials against a range of pathogensincluding Ngwith a key analog inhibiting andgtof Ng strains tested at extremely low concentrationsMICg mLPhotoaffinity labeling and biochemical experiments suggest that inhibition of trans translation is mediated through compound binding to a novel site of Elongation factor TuEF Tuan essential component of protein synthesis and trans translationacting selectively against trans translation over translationPreliminary evaluation of these compounds demonstrated limited cytotoxicity and a responsive SARenabling optimization of potency and resulting in the identification of MBXthe lead compound in this proposalThe objective of this Phase I application is to demonstrate that these trans translation inhibitors are effective in animal models of gonorrhea infection and build a dataset that will drive the transition from Hit to Lead to Lead OptimizationPhase II will focus on lead optimization to produce a preclinical candidate suitable for INDenabling studiesWe will achieve the Phase I objectives through four specific aimsIn Aimwe will chemically optimize the trans translation inhibitor series for potencyselectivity and in vitro ADME propertiestargeting chemical synthesis of andgtanalogsIn Aimwe will identify analogs with ADME T and potency properties suitable for in vivo testinganalyzing potency and in vitro properties for all materials generated in AimIn Aimwe will confirm and further explore the mechanism and specificity of tetrazole inhibitor of trans translation in NgIn Aimwe will evaluate lead analogs for bioavailabilityacute toxicity and efficacy in murine models of Ng infection Project Narrative Gonorrheal infections are an urgent threatwith overthousand cases reported annually in the United States and antibiotic resistance to all approved therapies observed in the clinicMoreoverthe pipeline of new therapeutics targeting Neisseria gonorrhoeae is smallWe propose to establish the in vivo efficacy of a novel class of antibiotics that utilize a previously unexploited bacterial target to sidestep existing resistance mechanism and that display excellent potency against multi drug resistant Neisseria gonorrhoeaewith the ultimate goal of developing these compounds as therapeutics