Development of a Designer Proline-rich antimicrobial peptide Chaperone protein inhibitor (DPC) for treating multi-drug resistant urinary tract infections

Urinary tract infectionsUTIsare one of the most common hospital acquired infections and are often caused by multi drug resistantMDRbacterial pathogensMDR bacterial pathogens are associated with significant morbidity and mortalitycreating enormous healthcare and economic burdens due to variations in disease natural histories as well as the lack of effective therapeutic optionsTreatment option limitations are particularly relevant for MDR Gram negative pathogenssuch as Escherichia coli and Klebsiella pneumoniaewhich have shown a great propensity to challenge the clinical care of patientsArrevus is developing a novel approach to addressing complicated UTIs caused by MDR Enterobacteriaceae through the use of Designer Proline rich Antimicrobial peptide Chaperone protein inhibitorsDPCsderived from insects and selectively modifiedacting as inhibitors to one of the critical bacterial proteins responsible for bacterial protein foldingDnaKAs an adjuvant therapy to current antibioticsDPCs have the potential to provide a much improved treatment option for MDR Gramnegative bacterial infectionsPreliminary studies have displayed the potential of ARVthe lead DPCas an antibiotic potentiating agent against MDR Gram negative bacterial pathogensOur efforts have shown thatDPCs enhance antibiotic activityDPCs reduce bacterial burden in a UTI modelARVhas a favorable preliminary safety profileARVprovides an enhancement of the effects of antimicrobial agents through a novel MOAandARVhas demonstrable activity in murine MDR Gram negative bacteremia modelsCollectivelythese data support the continued development of AVRthrough an STTR Phase I program targeting proof of concept data for the use of ARVin the treatment of complicated UTIsThe proposed Phase I program will involve in vitro assessmentsincluding minimum inhibitory concentration assays and checkerboard assaysto characterize the activity of ARVwith and without legacy antibiotics against uropathogens and the evaluation of the potential of resistance development to ARVAimSuccessful completion of Aimwill identify an optimal ARVantibiotic pairingThis optimal combination will then be assessed in a mouse UTI model against several uropathogensAimARVactivity will be assessed alone and in combination with the antibiotic identified in Aimin order to determine bacterial burden reductionThis Phase I program will provide the necessary proof of concept data to support further development of ARVin a Phase II program that will center on extensive in vivo efficacy studies and preliminary safety studies Urinary tract infections create significant healthcare and economic burdensand the impact of these infections is increasing due to antibiotic resistanceArrevus is developing a new class antimicrobial peptides derived from insects that act via a novel mode of action to enhance the ability of antibiotics to treat infections caused by Gram negative antibiotic resistant bacteria