ProjectSummary Thecontrolofhighlyantimicrobialresistant(AMR)infectionslikemulti-drugresistantPseudomonasaeruginosa is a serious global public health concern. Multi-drug resistant P. aeruginosa are one of the top AMR micro- organisms, presenting a major challenge for infection control. Alternative interventions to traditional antimicrobialsareurgentlyneeded.Monoclonalantibodies(mAbs)targetinghighlyconservedproteinsrepresent animportantapproachagainstinfectiousdiseases.MAbscanbedeliveredimmediatelypriortohospitalization or a medical procedure to prevent or control infection. However, protein mAb delivery technology is severely limitedbyhighmanufacturingcosts,slowdevelopmentandlong-termproduction,andarequirementforseveral high-doseadministrations(mg/kg).TheselimitationstendtomakeproteinmAbdeliveryachallengeforgeneral administrationandrestrictitsadministrationtolimitedpopulations.OurteamhasdevelopedDMAbtechnology, atransformativeapproachthataddressesthesecriticalissuesthroughencodingmAbgenesintoanoptimized DNAplatformthatisadministereddirectlyinvivo.DMAbsreachprotectivelevelsinvivowithdirectantimicrobial activity rapidly, can be manufactured simply and quickly, can likely avoid cold chain requirements, and are highlycost-effectivecomparedtoproteinIgG.Inarecentstudy,wedemonstratedthatengineeredDMAbscan effectivelydelivermAbinvivotocontrolMDRP.aeruginosainfectioninmice(Patel,DiGiandomenicoetalNat. Comm. 2017). Our goal is to build on this work, through further enhancement in DMAb technology and to translatethisapproachintoastrategyforcontrolofantibioticresistantinfections.Weareproposingtoenhance thepropertiesofourwell-characterizedDMAblead-seriesdirectedagainstMDRP.aeruginosaandtodevelop morepotentformswithenhancedantigenbindingandreceptorengagementtocontrolinfection.Inthisproposal, wewillperformimportantstudiestosupporttranslationofthisapproachtolargeranimalsandultimatelytomove toINDsubmission.