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.
Aminoglycoside antibiotics are an important class of antibiotics that are used worldwide despite the high incidence of hearing loss as an unintended side-effect. This project will advance the development of a small molecule compound that can prevent the hearing loss associated with aminoglycoside therapy.