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

Project SummaryOver $billion is spent annually in the US treating chronicnon healing woundsmany of which face lifethreatening complications due to infectionsWound infections are difficult to treat due to the frequency of antibiotic resistance as well as the formation of biofilmsa community of bacteria covered by an extracellular polymeric substanceBiofilm related infections can result in a substantial increase in bacterial tolerance and resistance to antibiotics compared to their planktonic phenotypeGiven the issues of resistancethe complex nature of biofilmsand poor clinical outcomes associated with chronic woundsit is urgent that alternative treatments be developed to address the bacterial protective mechanisms that maintain these difficult to treat infectionsArrevus is pioneering a novel approach to provide an effective treatment option for chronic wound infections through the development of Designer Proline rich Antimicrobial peptide Chaperone protein inhibitorsDPCsARVArrevuslead DPCkills bacteria in two distinct waysiby disrupting the bacterial lipid membrane and iiby selectively inhibiting the chaperone protein DnaKDnaK is a ubiquitously expressed and highly conserved prokaryotic heat shock protein critical for bacterial survival in stress conditions and is associated with bacterial biofilm formationPreliminary studies show that ARVhas anti infective capabilities both alone and in combination with other small molecule antibioticscan re sensitize multidrug resistantMDRbacteria to antibioticsdoes not exhibit off target binding to the human homologHspandhas reduced bacterial load and enhanced healing in several wound infection modelsIn this Phase I STTRArrevus will obtain proof of concept data to support the use of ARVas a therapeutic option for treating multidrug resistant wound infectionsIn Aimwe will evaluate the in vitro efficacy of ARValone and in combination with clinically relevant antibiotics against MDR Saureus and Paeruginosatwo microbes commonly associated with wound infectionsIn AimAwe will determine the antimicrobial efficacyand in AimBwe will determine the anti biofilm activityIn Aimwe will assess the antibiofilm and antimicrobial capabilities of ARValone and in combination with a clinically utilized antibiotic using the rabbit ear wound modelin collaboration with Robert GalianoM DNorthwestern UniversityThe rabbit ear model is clinically relevant and will allow us to determine the anti biofilm properties of ARValoneAimAand in combination with a synergistic antibiotic determined in AimAimBSuccessful completion of the proposed studies will provide the necessary efficacy data to support further development of ARVas a therapeutic agent for treating wound infections in Phase IIDevelopment of an ARVantibiotic treatment for chronic wound infections has the potential to provide an alternative strategy to address these hard to treat infections and enhance patient outcomes Project Narrative Chronic wounds are a significant healthcare burden and often complicated by infectious agents which can develop antibiotic resistance or form biofilmsBoth antibiotic resistance and biofilm formation complicate wound treatment and healingleading to poor clinical outcomesArrevus 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 wound infections caused by Gram negative and Gram positive antibiotic resistant bacteria