Ototoxicity of modified aminoglycosides

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PROJECT SUMMARY Aminoglycosides are one of the cheapest and well-known antibiotics in clinical use for over 70 years, but one of the major limitations in their use is their ototoxicity. Although new generations of antibiotics have emerged in the last decades, aminoglycoside antibiotics maintain a leading role in treatment of acute infections and for specific indications such as tuberculosis or the containment of pseudomonas bacteria in patients with cystic fibrosis. Owing to their broad antibacterial spectrum and efficacy against resistant bacterial diseases, aminoglycoside antibiotics continue to be indispensable. However, their use has been limited due to side effects. The major side effects accompanying aminoglycoside treatment are nephrotoxicity and ototoxicity, including cochlear damage and vestibular disorders. Nephrotoxicity affects about 20% of patients and is usually reversible, while ototoxicity is irreversible. It is estimated that cochlear damage occurs in 20% and vestibular disorders in 15% of those receiving aminoglycoside antibiotics, but the incidence increases markedly to 80% in long-term treatment for tuberculosis. The pathological feature of aminoglycoside-induced ototoxicity is loss of mechanosensory hair cells in the inner ear. Hair cell loss begins at the base of the cochlea and proceeds toward the apex. Hair cells are specialized mechanoreceptors that convert auditory and vestibular mechanical stimuli into electrical signals. These cells are responsible for the detection of sound and equilibrium. Since mammalian hair cells lack the ability to regenerate, the loss of or damage to hair cells is the leading cause of permanent hearing impairments and vestibular disorders. Although a series of biological events and cell death pathways are known to be involved in aminoglycoside-induced hair cell death, no established clinical therapies for prevention or amelioration of this disability are available. Aminoglycoside-induced ototoxicity reduces the quality of life of millions of affected individuals and confers a great economic cost. Therefore, development of new efficacious synthetic aminoglycoside derivatives, but without the problematic side effects, will provide a fundamental approach to prevent ototoxicity. Since the ototoxicity potential and organ preference varies among the different aminoglycoside antibiotics, small changes in structure may greatly influence toxicity, providing great possibility to find new aminoglycoside derivatives. We are developing fast and low-cost methods to develop aminoglycosides with broad spectrum anti-infective activities, but with reduced ototoxicity. In this project, we will identify novel aminoglycoside based anti-infectives, that show reduced ototoxicity. This work addresses an important health issue, anti-infective drug ototoxicity, and presents creative steps towards a novel solution to this problem. Unless innovative strategies are developed to produce robust and effective new classes of non-toxic antibiotics, health care costs will continue to climb and we will completely lose our ability to combat even the most common infection. One of the challenges of research in drug development is to find ways to use the increasing knowledge of the mechanisms underlying disease biology, and toxicities, along with disease transformation and progression to develop novel therapeutic strategies for MDR, XDR, and PDR infections. One of the biggest bottlenecks in the advancement of drugs to the clinic and eventual limitation in the clinical usage, is the toxicity of the drug. This problem becomes even more acute when the drugs have to be used for extended periods of time (months), such as for fungal infections in immunocompromised patients. We have therefore focused our efforts in identifying the toxicity pathways for individual drug classes, such as aminoglycosides, and addressed these issues at the very outset. Since aminoglycoside-induced hair cell loss in explants is similar to that in humans, we will first use mouse organ culture for a secondary screening of the top compounds without toxicity. We will then use pigmented guinea pigs to evaluate auditory function by measurement of auditory brainstem responses, count loss of sensory hair cell loss, and assess renal function with serum for the top compounds. The results of this project will help us identify novel aminoglycosides with high efficacy against microbes of interest, but with reduced toxicity. The work proposed here, a multidisciplinary effort using rapid methods of synthesis, inhibition, and ototoxicity assays, will be further developed in this Phase II application using in vivo efficacy and ototoxicity studies using guinea pig models. We propose using novel aminoglycoside modifications, patented NUBAD assays, mouse organ culture studies, guinea pigs, to identify conjugates that show reduced ototoxicities, opening possibilities for developing drugs that can target resistant pathogens, but with much improved therapeutic indices.