The main aims

Aminoglycoside antibiotics (AGs) are highly efficacious antibiotics, the application of which has been severely curtailed by significant nephrotoxic and ototoxic side effects. While kidney damage is often reversible, hearing damage in patients treated with AGs is permanent. Nevertheless, AGs have in recent years regained high clinical importance due to the emergence of multidrug-resistant (MDR) pathogens, as a mainstay for the treatment of such serious infections. Administered commercial AGs most often consist of a mixture of small molecules (congeners). Interestingly, studies on 4 gentamicin congeners indicate that individual AG congeners may exhibit different toxicities. Isolation of a whole array of single AG congeners with anti-infective activity would provide a whole new series of AG antibiotics to be tested for their ototoxicity and nephrotoxicity, potentially enabling the identification of AGs with reduced toxicity.

The main aims of this project are:
1) Isolation of congeners present in commercial AG mixtures.
2) Identification of effective congeners that lack the detrimental effects leading to hearing loss.

Why the research is important and timely

In the recent years, the prevalence of multidrug-resistant-pathogens has been high and rising. The antibiotics currently in use are losing their power and the clinical pipeline is lean. To address this mounting challenge of infections by MDR-pathogens, clinicians have returned to some potent antibiotics that were used in the past, such as AGs. Unfortunately, this class of antibiotics shows an unacceptably high risk of side effects, most notably nephro- and ototoxic. These considerations underline the importance of finding ways to attenuate AG-induced toxicity, and thus avoid permanent hearing impairment in many patients receiving life-saving treatments.
Additionally, while separation of individual compounds from complex mixtures was until recently not feasible, new technological developments are making it now possible to isolate single compounds at an industrial scale without vastly increasing production costs, attracting the interest of the Pharma industry.

Who might benefit from the research outcomes and how

Despite their adverse side effects, there are a good number of instances in which administration of AGs is practically obligatory, e.g. against MDR infections; they are also employed to treat cystic fibrosis patients. In addition, their low production cost makes them drugs of choice in developing countries. These facts, together with the observations that nearly half of the individuals who have at some point received AG treatment experiment hearing deficits, and that there is a clear increase in the number of MDR-pathogens, highlight the relevance of the proposed project as an avenue to reduce the incidence of hearing loss in the general population. Decreased ototoxicity of AGs would directly benefit groups of patients such as those mentioned above (i.e. cystic fibrosis patients, individuals suffering MDR bacterial infections, pre-term neonates in neonatal intensive care units), most especially those who are HIV-positive or who have a genetic predisposition to developing AG-induced hearing loss. Furthermore, development of new AGs that lacked the detrimental side effects of the currently available AGs would allow the full exploitation of AGs’ anti-infective potential in the clinic.