SBIR-STTR Award

Cystic fibrosis (CF) is the most common life shortening inherited disorder amongst Caucasians, and Pseudomonas aeruginosa pulmonary infections are the leading cause of mortality in CF patients. Treatment of patients infected with P. aeruginosa is complicated by the cell-to-cell signaling systems of this organism, which regulate biofilm formation, virulence genes, and antibiotic resistance genes such as efflux pumps. These mechanisms augment bacterial resistance to both antibiotics and host defense, causing a vicious cycle in which the body's immune system continuously mounts an unproductive assault on bacterial infection, resulting in chronic inflammation, tissue damage, and eventually respiratory failure. The co-founders of Agile Sciences, Inc. have discovered simple derivatives of sponge-derived marine natural products with unprecedented activity toward inhibiting and dispersing bacterial biofilms. These ""Agilyte"" compounds work synergistically with antibiotics to reduce bacterial growth and lower the MICs of antibiotics toward antibiotic-resistant bacteria. In preliminary work, Agilyte molecules have shown efficacy toward: 1) inhibiting and dispersing biofilms of P. aeruginosa at low-micromolar concentrations and 2) working synergistically with tobramycin to stop growth of P. aeruginosa in broth culture. The goal of this proposal is to assess the efficacy of Agile Sciences'lead Agilyte compounds in an in vivo mouse model of chronic P. aeruginosa infection developed by Dr. Richard Boucher at UNC Chapel Hill. To this end, the Specific Aims of this Phase I STTR Project are: 1. To perform advanced in vitro studies of 5 Agilyte compounds to inform lead compound selection for in vivo studies. 2. To evaluate efficacy of two lead compounds selected in Specific Aim #1 in the Boucher mouse model of chronic P. aeruginosa pulmonary infection. Dr. Laura Guogas, a microbiologist with expertise in cystic fibrosis pulmonary disease, will lead the in-house efforts t Agile Sciences as well as coordinate a team of expert collaborators. Testing of Agilyte molecules in vivo will be conducted in the laboratory of the co-PI, Dr. Richard Boucher, the Kenan Professor of Medicine and Cystic Fibrosis and Pulmonary Research and Treatment Center Director at UNC. Guidance on preclinical development of the Agilyte molecules will be provided by Dr. Ward Peterson, former Vice President of Research and Preclinical Development at Inspire Pharmaceuticals, a biotechnology company formerly focused on CF therapeutics. Agile co-founder Dr. Christian Melander will provide expertise on the biological properties of the Agilyte molecules. This multidisciplinary team will work cooperatively to assess the potential of Agile's novel technology to decrease P. aeruginosa proliferation under in vivo conditions relevant to the CF lung. If successfully developed, our proposed therapeutic has the potential to modulate the significant mortality and morbidity associated with CF disease through the eradication of chronic bacterial infection.

Public Health Relevance:
Developing therapeutics to treat cystic fibrosis (CF) is especially challenging due to the formation of communities of bacteria called biofilms in the lungs of cystic fibrosis patients. Agile Sciences is developing molecules that both inhibit and disperse bacterial biofilms and thus have the potential to significantly enhance the effectiveness of antibiotic therapy for CF. An improved treatment for CF has the potential to both extend the life expectancy and improve the quality of life for the hundreds of thousands of individuals worldwide who are living with CF.

Thesaurus Terms:
Antibiotic Agents;Antibiotic Drugs;Antibiotic Resistance;Antibiotic Therapy;Antibiotic Treatment;Antibiotics;Bacteria;Bacteria Resistance;Bacteria Resistant;Bacterial Infections;Bacterial Resistant;Bioavailability;Biologic Availability;Biological;Biological Availability;Biotechnology;Body Tissues;Cf Lung Disease;Cf Mice;Cf Mouse Model;Cf Patients;Caucasian;Caucasian Race;Caucasians;Caucasoid;Caucasoid Race;Cell Communication And Signaling;Cell Signaling;Cells;Chronic;Clinical Drug Development;Clinical Drug Testing/Development;Collaborations;Communities;Consultations;Cystic Fibrosis;D-Streptamine, O-3-Amino-3-Deoxy-Alpha-D-Glucopyranosyl-(1-6)-O-(2,6-Diamino-2,3,6-Trideoxy-Alpha-D-Ribo-Hexopyranosyl-(1-4))-2-Deoxy-;Data;Development;Disease;Disorder;Effectiveness;Evaluation;Generalized Growth;Genes;Goals;Growth;Host Defense;Housing;Immune System;In Vitro;Inborn Genetic Diseases;Individual;Infection;Inflammation;Inherited Disorder;Intracellular Communication And Signaling;Loinc Axis 2 Property;Loinc Axis 4 System;Laboratories;Lactamase;Lead;Life;Life Expectancy;Lung;Lung Respiratory System;Lung Diseases;Lytotoxicity;Measures;Medicine;Microbial Biofilms;Miscellaneous Antibiotic;Morbidity;Morbidity - Disease Rate;Mortality;Mortality Vital Statistics;Mucous Body Substance;Mucoviscidosis;Mucus;Multi-Drug Resistance;Multidrug Resistance;Multiple Drug Resistance;Multiple Drug Resistant;Nebramycin Factor 6;North Carolina;Occidental;Organism;P. Aeruginosa;P.Aeruginosa;Patient Care;Patient Care Delivery;Patients;Pb Element;Permeability;Pharmaceutical Agent;Pharmaceuticals;Pharmacologic Substance;Pharmacological Substance;Phase;Physiologic Availability;Play;Porifera;Property;Pseudomonas Aeruginosa;Pseudomonas Pyocyanea;Pulmonary Cystic Fibrosis;Pulmonary Diseases;Pulmonary Disorder;Qol;Quality Of Life;Research;Research Proposals;Resistance To Multi-Drug;Resistance To Multidrug;Resistance To Multiple Drug;Resistance To Antibiotics;Resistant To Multiple Drug;Resistant To Antibiotics;Resistant To Multi-Drug;Resistant To Multidrug;Respiratory Disease;Respiratory Failure;Respiratory System Disease;Respiratory System Disorder;Role;Sttr;Safety;Science;Signal Transduction;Signal Transduction Systems;Signaling;Small Business Technology Transfer Research;Sponges;Sponges (Zoology);System;Technology;Testing;Therapeutic;Tissue Growth;Tissues;Tobramycin;Tobrex;Toxic Effect;Toxicities;Universities;Up-Regulation;Up-Regulation (Physiology);Upregulation;Virulence;Work;Airway Epithelium Infalmmation;Airway Inflammation;Allergic/Immunologic Body System;Allergic/Immunologic Organ System;Antibiotic Resistant;Assault;Bacterial Disease;Bacterial Disease Treatment;Bacterial Infectious Disease Treatment;Bacterial Resistance;Biofilm;Biological Signal Transduction;Cystic Fibrosis Lung Disease;Cystic Fibrosis Mouse;Cystic Fibrosis Mouse Model;Cystic Fibrosis Patients;Cytotoxicity;Derepression;Developmental;Disease/Disorder;Drug Discovery;Efflux Pump;Experiment;Experimental Research;Experimental Study;Extracellular;Genotoxicity;Heavy Metal Pb;Heavy Metal Lead;Improved;In Vitro Testing;In Vivo;In Vivo Model;Inborn Error;Living System;Lung Disorder;Marine Natural Product;Mouse Model;Mucous;Multi-Drug Resistant;Multidisciplinary;Multidrug Resistant;New Technology;Novel;Novel Technologies;Ontogeny;Pathogen;Patients With Cf;Patients With Cystic Fibrosis;Physical Property;Pre-Clinical;Pre-Clinical Research;Preclinical;Preclinical Research;Professor;Pulmonary;Research Study;Resistance Mechanism;Resistance To Bacteria;Resistance To Bacterial;Resistant Mechanism;Resistant To Bacteria;Resistant To Bacterial;Respiratory Insufficiency/Failure;Social Role;Treatment Center;Ward;White Race

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 1000 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 2-aminoimidazole (2-AI) compound, AGL-503, 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-503 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 Boucher's lab at the University of North Carolina at Chapel Hill, AGL-503 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 1 to enhance the activity seen with AGL-503. 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/2-AI combination identified in Aim 1 will be further evaluated in Aim 2 using Dr. Boucher'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 2-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 Statement:


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.

Project Terms:
Address; Adjuvant; Aerosols; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; antimicrobial; Area; Back; Bacteria; Biological Assay; Caco-2 Cells; Cells; Clinical; Clinical Trials; Combined Antibiotics; Communities; Cystic Fibrosis; cystic fibrosis mouse; cystic fibrosis patients; Data; Defense Mechanisms; Development; Dose; Drug Kinetics; Drug resistance; effective therapy; Effectiveness; Elements; Enzymes; Evaluation; Failure (biologic function); Goals; Immune; improved; In Vitro; in vitro Assay; in vivo; Individual; Infection; Infiltration; intravenous administration; Lead; Life Expectancy; Lung; Measures; Metabolic; Microbial Biofilms; Microbiology; Minimum Inhibitory Concentration measurement; Modeling; Mortality Vital Statistics; Multi-Drug Resistance; Mus; North Carolina; novel; novel therapeutics; Organic Chemistry; Organism; Patients; Performance; Permeability; Pharmaceutical Chemistry; Pharmacodynamics; Pharmacologic Substance; Phase; phase 1 study; phase 2 study; Porifera; pre-clinical; Prevalence; Program Development; programs; Property; Pseudomonas aeruginosa; public health relevance; Quality of life; Regimen; Research Personnel; Resistance; resistant strain; Route; Safety; scaffold; Schedule; Science; Sea; signal processing; Small Business Technology Transfer Research; small molecule; Solutions; Sputum; Staging; Structure; Surface; Technology; Testing; Therapeutic; therapy development; Time; Toxic effect; Treatment Failure; Universities; Work