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Development of a predictive moderate throughput assay to screen novel Designer Proline-rich antimicrobial peptide Chaperone protein inhibitors (DPCs) against multi-drug resistant pathogen

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AI142829-01
Agency Tracking Number: R41AI142829
Amount: $299,248.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA18-575
Timeline
Solicitation Year: 2018
Award Year: 2019
Award Start Date (Proposal Award Date): 2018-12-01
Award End Date (Contract End Date): 2020-11-30
Small Business Information
2 DAVIS DR
Research Triangle Park, NC 27709-0003
United States
DUNS: 080059821
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 CARL KRAUS
 (919) 366-5501
 ckraus@arrevus.com
Business Contact
 JEFFREY SMITH
Phone: (919) 366-5502
Email: jsmith@arrevus.com
Research Institution
 MONTANA STATE UNIVERSITY - BOZEMAN
 
309 MONTANA HALL
BOZEMAN, MT 59717-0000
United States

 Nonprofit College or University
Abstract

Multi drug resistantMDRbacterial infections represent a significant threat to public healthIt is estimated that the impact of antibiotic resistance will continue to grow resulting in a global economic burden of $trillion and causingmillion deaths annuallyMany of the therapeutics currently under development represent traditional antibiotic approaches or next generation antibiotics that will likely suffer a limited market lifespan due to the rapid emergence of resistanceTo effectively address antibiotic resistance and have therapeutic options that are effectiveapproaches that utilize new mechanisms of action must be exploredArrevus is developing a novel approach to addressing MDR bacterial infections using 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 foldingDnaKPreliminary studies have demonstrated the potential of DPCs as antibiotic potentiating agents against MDR gram positive and gram negative bacterial pathogensOur efforts have shown that DPCsenhance antibiotic activityreduce bacterial burden in systemic infection modelshave favorable preliminary safety profilesandprovide an enhancement to antimicrobial agents through a novel mechanism of actionWhile early efforts to develop DPCs has been successfulthe pace of the programs and expansion into additional indications has been hindered due to the lack of reliable in vitro screening assays that correlate with in vivo efficacyDPCs that have displayed potency using minimum inhibitory assays have failed in subsequent in vivo efficacy studiesThe objective of the proposed Phase I program is to develop and validate an in vitro assay for DPC activityIn Aima scratch test assay using human alveolar and keratinocyte cells will be characterized for several endpointsincluding scratch closurecytokine productionand apoptosis in the presence of well characterized DPCs and antibiotics to develop an assay that is predictive of in vivo DPC activityIn Aimthe assay developed in Aimwill then be used to inform a medical chemistry program that is designed to identify DPCs with activity against methicillin resistant Staphylococcus aureusTwo lead DPCs identified using the using the assay will then be evaluated for in vivo efficacy using a standard thigh infection modelSuccessful completion of the proposed program will provide proof of concept for the use of the developed in vitro assay for detecting DPC activity that is predictive of in vivo activity and will support a Phase II program that will expand the assay to use with gramnegative pathogens and evaluate lead DPCs in indication specific models Project Narrative Antibiotic resistant infections are associated with an increased morbidity and mortality compared to antibioticsensitive infections and represent a significant threat to public healthArrevus is developing a new class of antiinfectivesmodified antimicrobial peptidesderived from insects that act via a novel mode of action to enhance the ability of antibiotics in treating antibiotic resistant infectionsArrevus proposes to develop an in vitro assay that will predict in vivo efficacy of the modified antimicrobial peptides in order to expedite development programs for multi drug resistant infections

* Information listed above is at the time of submission. *

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