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Anti-biofilm agents for the treatment of pulmonary infection in cystic fibrosis p

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R42AI098192-02A1
Agency Tracking Number: R42AI098192
Amount: $1,499,094.00
Phase: Phase II
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA13-235
Timeline
Solicitation Year: 2014
Award Year: 2014
Award Start Date (Proposal Award Date): 2014-07-15
Award End Date (Contract End Date): 2016-06-30
Small Business Information
1791 Varsity Dr., Raleigh, NC, 27606-2576
DUNS: 828576202
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 DAVID JUNG
 (919) 484-0730
 djung_1@yahoo.com
Business Contact
 EVA GARLAND
Phone: (919) 961-8919
Email: egarland@agilesci.com
Research Institution
 UNIV OF NORTH CAROLINA CHAPEL HILL
 CHAPEL HILL, NC, 27599-0001
 Nonprofit college or university
Abstract
DESCRIPTION provided by applicant The leading cause of mortality in patients with cystic fibrosis CF is pulmonary failure from lung infections and the predominant organism isolated from these infections is the bacterium Pseudomonas aeruginosa Lung infections of CF patients persist over the lifetime of the patients and are impossible to eradicate due to the ability of bacteria to form biofilms and to express multidrug resistance elements Biofilms are surface attached communities of bacteria that are surrounded by a protective matrix Bacteria in biofilms are upwards of times more resistant to currently used antimicrobials than free floating bacteria In addition to the ability of P aeruginosa to form biofilms the bacterium is known to rapidly acquire resistance to antibiotics to form multidrug resistant MDR strains Due to the inherent limitations of current therapies to effectively eliminate P aeruginosa biofilms and MDR P aeruginosa from the lungs of CF patients an improved therapeutic option is needed that addresses these underlying reasons for treatment failure In Phase I Agile Sciences identified a lead aminoimidazole AI compound AGL that is effective at dispersing MDR P aeruginosa biofilms in vitro and in vivo and enhancing antibiotic efficacy toward MDR P aeruginosa as measured by a lowering of the MIC value of the antibiotic AGL is a small organic molecule that acts via a novel mechanism of action and possesses therapeutically desirable permeability toxicity and metabolic stability properties Furthermore in an in vivo evaluation in Dr Richard Boucherandapos s lab at the University of North Carolina at Chapel Hill AGL was shown to disrupt biofilm like aggregates of bacteria within the lungs of mice In Phase II of this STTR project a medicinal chemistry effort will be used in Aim to enhance the activity seen with AGL Agile Sciences has assembled a team of pharmaceutical experts in the areas of microbiology organic chemistry pharmacokinetics pharmacodynamics toxicity and pre clinical development to guide the medicinal chemistry program The optimal antibiotic AI combination identified in Aim will be further evaluated in Aim using Dr Boucherandapos s murine model to maximize the efficacy of the combination treatment Specific variables to be evaluated include route of administration as well as dosing schedule Dr Matt Wolfgang will join the Phase II team as a co investigator adding additional expertise in P aeruginosa lung infection models Upon completion of this work Agile Sciences expects to have identified a candidate AI molecule that will then enter a preclinical development program consisting of GLP safety assessments to enable IND submission to the FDA and subsequent clinical trials The novel therapy developed in this Phase II work has the potential to substantially enhance current therapeutic performance toward recalcitrant P aeruginosa lung infections in the lungs of CF patients thereby increasing the quality of life and life expectancy of these individuals PUBLIC HEALTH RELEVANCE The primary cause of mortality of CF patients is complications associated with untreatable lung infections The difficulty in treating these infections is due bot to the presence of biofilms which are communities of bacteria surrounded by a protective matrix and to the arsenal of drug resistance enzymes the bacteria harbor This project addresses the inherent limitations of antibiotic therapies for CF patients by co dosing the antibiotics with a novel adjuvant therapeutic that is capable of disrupting biofilms and enhancing the effectiveness of the antibiotic

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

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