Use of a Designer Proline-rich antimicrobial peptide Chaperone protein inhibitor (DPC) for treating antibiotic resistant pneumonia

Project SummaryInfectious disease is the third leading cause of death in the United Statesand hospital acquired infectionsHAIsin particular affectmillion patients annuallyThe most common type of HAI is pneumoniaoften caused by multi drug resistantMDRpathogens such as Staphylococcus aureusPseudomonas aeruginosaKlebsiella pneumoniaeEscherichia coliand Acinetobacter baumanniiRates of antibiotic resistance for these bacteria in hospitaland ventilator acquired pneumoniaHAP and VAPrespectivelyhave escalated significantlyin some cases exceedingThere is a clear and urgent unmet medical need for new therapeutic strategies to treat HAP and VAP that can improve patient outcomes and combat the rising rates of antibiotic resistance associated with HAIsAs a novel approach to address this expanding medical needArrevus is pioneering the development of Designer Proline rich antimicrobial peptide Chaperone protein inhibitorsDPCsThe lead compoundARVimparts its antimicrobial activity in two distinct waysidisrupting the bacterial lipid membrane and iispecifically inhibiting the bacterial chaperone protein DnaKa highly conserved prokaryotic heat shock protein critical for bacterial survival in stress conditionsIn preliminary studiesARVhas demonstrated broad spectrum antimicrobial activity against a range of Gram negative and Gram positive bacterial pathogensARVhas also demonstrated the ability to reverse bacterial resistance to legacy antibioticsIn the proposed Phase I programArrevus will conduct a series of studies to characterize the antibiotic activities of ARVboth in vitro and in vivo in order to assess the potential of ARValone and in combination with an antibioticto treat HAP and VAPIn Aimwe will use in vitro studies to define the spectrum of activity of ARValoneAimAand in combination with clinically utilized antibioticsAimBagainst antibiotic sensitive and antibiotic resistant strains of PaeruginosaIn Aimwe will assess ARValone and as an adjuvant therapy with the meropenem in a mouse model of pneumoniaIn AimAARVwill be administered as a monotherapy to characterize efficacy and dosing for co treatment in AimBThe collective data from this Phase I effort will define ARVs abilityalone or with an antibioticto treat pneumonia that is typically resistant to legacy antibioticsThese proof of concept data are critical to support further development of ARVin a Phase II program that would be geared toward performing extensive in vivo efficacy and safety studies to assess ARVas a therapeutic option for treating MDR associated HAP and VAP Project Narrative The prevalence of hospitaland ventilator acquired pneumonia is highwith infections becoming increasingly difficult to treat due to rising rates of 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 pneumonia caused by Gram negative antibiotic resistant bacteria