SBIR-STTR Award

Aminoglycoside antibiotics (AGs) are important for the treatment of a variety of serious infectious diseases including septicemia, complicated intra-abdominal infections, complicated urinary tract infections, and nosocomial respiratory tract infections. AGs are the mainstay of treating Pseudomonas infection in patients with cystic fibrosis and one of the best classes of medication for treating multiple drug resistant TB throughout the world. AGs would be even more widely used today if it were not for the fact that as many as 20% of patients treated with AGs develop measurable irreversible hearing loss and a significant fraction of these people become functionally deaf. This side effect, called ototoxicity, has made what would otherwise be a cheap and effective antibiotic into a treatment of last resort. Screening chemicals in a zebrafish model has identified a small molecule compound that has been shown to prevent hair cell death in the zebrafish and also to be effective in preventing hearing loss in rats treated with AGs. Additional chemical modifications have yielded three classes of compounds that are up to 100x more potent in the zebrafish screens and have acceptable safety profiles to merit further development as medicinal candidates. There is funding to confirm that these new compounds protect against the ototoxic effects of aminoglycosides in rats. The goal of this SBIR phase-1 grant is to progress the efficacious compounds towards human trials by demonstrating first in vitro that they do not interfere with the bactericidal efficacy of the AGs, next by confirming that they are not toxic in cell cultures and finally by confirming the in vivo safety profile of the lead compound using industry standard dose-range finding toxicology studies in rats with doses going to many multiples of the efficacious dose. Proof of concept that one of more of these chemicals is both effective and safe would allow taking the lead compound through API manufacturing and GLP-toxicology studies, an FDA Investigational New Drug approval and eventually to approval for use as an adjunct therapy in humans taking AGs.

Thesaurus Terms:
Abdominal Infection;Acinetobacter;Acute Toxicity Tests;Advanced Development;Adverse Effects;Aerobic;Affect;Amikacin;Aminoglycoside Antibiotics;Aminoglycoside-Induced Ototoxicity;Aminoglycosides;Anti-Bacterial Agents;Antibiotics;Applications Grants;Bactericide;Base;Biological Assay;Cell Culture Techniques;Cell Death;Cells;Chemicals;Chemotherapeutic Agent;Clinical;Clinical Practice;Clinical Trials;Communicable Diseases;Cystic Fibrosis Patients;Data;Deafness;Development;Dosage;Dose;Drug Candidate;Drug Exposure;Drug Formulations;Drug Resistant Tuberculosis;Drug Use Screening;Enterobacter;Experience;Fda Approved;Funding;Goals;Grant;Hair Cells;Health;Hearing;Hearing Impaired Persons;Hearing Impairment;Human;In Vitro;In Vivo;Incidence;Industry;Infection;Intellectual Property;Intra-Abdominal;Investigational Drugs;Labyrinth;Lateral Line;Lead;Legal Patent;Licensing;Malignant Neoplasms;Measurable;Methods;Microbial Alkaline Proteinase Inhibitor;Minimum Inhibitory Concentration Measurement;Modeling;Modification;Multi-Drug Resistance;Mycobacterium Tuberculosis;Nephrotoxicity;New Drug Approvals;Nosocomial Uti;Ototoxicity;Patients;Pharmaceutical Preparations;Phase;Phase I Clinical Trials;Plasma;Positioning Attribute;Prevent;Pseudomonas;Pseudomonas Aeruginosa;Pseudomonas Infections;Rattus;Research Clinical Testing;Research Design;Resort;Respiratory Tract Infections;Safety;Safety Study;Schedule;Scientist;Screening;Septicemia;Small Business Innovation Research Grant;Small Molecule;Testing;Therapeutic;Therapeutic Index;Therapeutic Uses;Tinnitus;Tobramycin;Toxic Effect;Toxicokinetics;Toxicology;Universities;Washington;Work;Zebrafish;

Aminoglycoside antibiotics (AGs) are important for the treatment of a variety of serious infectious diseases including septicemia, complicated intra-abdominal infections, complicated urinary tract infections, and nosocomial respiratory tract infections. AGs are the mainstay of treating Pseudomonas infection in patients with cystic fibrosis and one of the best classes of medication for treating multiple drug resistant TB throughout the world. AGs would be even more widely used today if it were not for the fact that as many as 20% of patients treated with AGs develop measurable irreversible hearing loss and a significant fraction of these people become functionally deaf. This side effect, called ototoxicity, has moved aminoglycoside antibiotics from what would otherwise be a cheap and effective therapy into a treatment of last resort. Previously, we identified a class of small molecular compounds that were effective at preventing hair cell death in the zebrafish and later showed them to also protect hearing and prevent inner ear hair cell death in rats exposed to high doses of AGs. Our Phase I SBIR grant enabled us to show that these compounds did not interfere with the bactericidal properties of AGs and have a wide margin of safety in a variety of standard in vitro safety tests. The Phase I work led to the selection of our leading clinical candidate. This Phase II project seeks to continue to advance our candidate through the required steps of GLP/GMP manufacturing of a medicine and through the rigorous safety testing dictated by the FDA for in-human trials. We have assembled a team of hearing experts, medicinal chemists, pharmacologists, infectious disease experts, toxicologists and regulatory experts to guide the project through FDA IND application and approval. The project will result in the first medicine ever approved by the FDA to prevent hearing loss of any type.

Public Health Relevance Statement:


Public Health Relevance:
Aminoglycoside antibiotics are an important class of antibiotics that are used worldwide to treat life-threatening infections, despite the high incidenc of hearing loss as an unintended side-effects. We have identified a new compound that prevents the hearing loss associated with aminoglycoside therapy. This project will advance the manufacture and test the safety of this compound according to the requirements of the FDA and submition of a US Investigation New Drug application.

Project Terms:
Abdominal Infection; Adverse effects; Aerobic; Affect; Aminoglycoside Antibiotics; Aminoglycosides; Antibiotics; bactericide; Canis familiaris; Cell Death; chemotherapeutic agent; Clinical; Clinical Research; Communicable Diseases; cystic fibrosis patients; Data; Disease; dosage; Dosage Forms; Dose; Drug Kinetics; Drug resistance in tuberculosis; drug use screening; effective therapy; equilibration disorder; FDA approved; Goals; Grant; Hair Cells; Hearing; Hearing Impaired Persons; hearing impairment; Hearing problem; Human; In Vitro; in vivo; Incidence; Infection; Intellectual Property; Intra-abdominal; Intravenous; Investigation; Labyrinth; lateral line; Lead; Legal patent; Licensing; Life; Malignant Neoplasms; Measurable; Medicine; meetings; Methods; Molecular; Multi-Drug Resistance; Multiple drug resistant Mycobacteria Tuberculosis; mycobacterial; Mycobacterium tuberculosis; nephrotoxicity; nosocomial UTI; novel therapeutics; Oral; ototoxicity; Pamphlets; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phase II Clinical Trials; Physicians; preclinical study; prevent; Property; Pseudomonas; Pseudomonas Infections; public health relevance; Rattus; Reporting; Research Personnel; Resort; Respiratory Tract Infections; Safety; safety study; safety testing; Schedule; Septicemia; Small Business Innovation Research Grant; small molecule; South Africa; Testing; Therapeutic; Therapeutic Agents; Therapeutic Uses; therapy duration; Toxicology; treatment choice; Universities; Washington; Work; Zebrafish