Development of a novel agent to treat antimicrobial resistant Neisseria gonorrhoeae

The WHO estimates gonorrhea infections occur inmillion people globally every yearThe extensive spread of antimicrobial resistant Ng has prompted the CDC to designate it as an Urgent Threat pathogenAlarminglyresistance is now emerging to the remaining current standard of careSOCdual therapy of ceftriaxoneCROand azithromycinAZMDespite this global health crisisfew new therapeutic agents are currently under clinical development to treat AMR NgThusnew agents with novel mechanisms of actionMOAnot cross resistant to existing drug classes and not themselves susceptible to rapid resistance selection are needed to address the clinical spread of AMR NgOur proposal aims to develop a new AMR Ng therapeutic with a novel MOA not previously exploited in a clinical setting to treat GCthereby replacing the SOC agentCROand in doing so address the most serious threat of CRO resistant NgWe recently identified a novel and patentable analog of the natural product Moenomycin AMoeAwe name MedinamycinMedMWhereaslactams like CRO inhibit penicillin binding proteinPBPmediated transpeptidation of peptidoglycanPGpolymersMedM acts as a PBP transglycosylationTGinhibitor that abolishes PG synthesisMedM displays exceptional Ng activityMIC rangeug mlcomparable to CROpotent bactericidal activityand a low frequency of resistanceFOR andltxsimilar to MoeAMedM also exhibits an advantageous pharmacokinetic profilehighlighted by good subcutaneous exposure and long half life anticipating single dose efficacy against AMRNgBuilding upon a solid foundation of preliminary dataour Aims areAimPhasePhEstablish MedM MOA in Ng and development potential as a novel GC agentMilestoneObtainmg of MedM and demonstrate directly in Ng that MedMAZM FICI andltMedM FOR andltxMedMR mutants map to Ng PBP TG active siteand MICandltug ml acrossclinical isolatesAcceptable in vitro toxicity and minimal off target activityEstablish dose ranging for in vivo modelsEfficacy POC is achieved with favorableprotective dose for survivalandltmg kgfordaysAimPhasePhEstablish MedM suitability for critical in vivo modelingMilestoneDevelop fermentation to provideg MedMdemonstrate MICequal or superior to ETXandltug mlindiverse AMR Ng clinical isolatesand identify a formulation using a safety approved vehicle that achievesx MICexposure in relevant species for in vivo efficacy models described in AimAimPhEstablish MedM as a drug development candidate to treat GCEvaluate compound efficacy in a murine female gonococcal lower genital tract infectionFGLGTIand Saureus deep thigh infection modelMilestoneDemonstrate that MedM achievesclearance in FGLGTI models andltdays IM treatment and andgtlog reduction in murine deep thigh infection model withinh IM treatment Narrative NgonorrhoeaeNgis an obligate Gram negative human pathogen and causative agent of sexually transmitted gonorrheaThe extensive spread of antimicrobial resistant Ng has prompted the CDC to designate it as an Urgent Threat pathogenThis project will develop a therapeutic with a novel mechanism of action to combat antimicrobial resistant Ng