Sussex Neuroscience

Professor Corne Kros

CorneMechanisms and prevention of drug-induced ototoxicity

Our sense of hearing depends on the correct functioning of hair cells, the cells in the inner ear that convert sounds such as speech and music into electrical signals that the brain can interpret. The aminoglycoside antibiotics, of which gentamicin is the most widely used, combat serious infections but have the unfortunate side-effect of causing damage to these hair cells, so that some 25% of treated patients are left with measurable hearing loss. Likewise, the anti-cancer medicine cisplatin is highly effective in degrading solid tumours (e.g. curing over 90% of cases of testicular carcinoma), but at the cost of permanent hearing loss in almost all patients. We discovered that aminoglycosides enter hair cells mainly through their mechano-electrical transducer (MET) channels situated at the top of the bundles of ‘hairs’ or stereocilia, by acting as permeant blockers. Once inside the cells the drug molecules remain trapped and cannot exit. Less is known about how cisplatin enters hair cells, but the MET channels are one option. Research in the Kros lab aims:
(i) to characterize, at a molecular level, the drug binding sites in the MET channel pore, recently identified as TMC1,
(ii) to identify and develop other blockers of the MET channel that might be otoprotective by competing with the drugs for entry into the hair cells.
Various projects are possible in this area, depending on your interests. For example, the student could employ electrophysiological methods to study the interaction of ototoxic drugs and/or candidate otoprotective compounds with the MET channels (whole-cell patch-clamp recordings of MET currents elicited by a fluid jet from mouse cochlear hair cells). Confocal microscopy can be used to study the entry of fluorescently labelled versions of the ototoxic drugs into the hair cells. My lab collaborates closely with that of Guy Richardson, also in Sussex Neuroscience, which offers access to a range of cell biology techniques, as well as with members of the Sussex Drug Discovery Centre, who design and optimize protective compounds.
The project would suit a student who is interested in understanding the molecular mechanisms of mechanotransduction by auditory hair cells, and using that understanding to develop novel drugs that protect hearing.

Selected publications:
1. Marcotti, W., Netten, S.M. van & Kros, C.J. (2005). The aminoglycoside antibiotic dihydrostreptomycin rapidly enters hair cells through the mechano-electrical transducer channels. Journal of Physiology 567, 505-521.
2. Netten, S.M. van & Kros, C.J. (2007). Insights into the pore of the hair cell transducer channel from experiments with permeant blockers. In Current Topics in Membranes, Vol. 59: Mechanosensitive Ion Channels, Part B, ed. Hamill, O.P., pp. 375-398. Academic Press, New York.
3. Corns, L.F., Johnson, S.L., Kros, C.J., & Marcotti, W. (2016). TMC1 point mutation affects Ca2+ sensitivity and block by dihydrostreptomycin of the mechanoelectrical transducer current of mouse outer hair cells. Journal of Neuroscience 36, 336-349. doi: 10.1523/JNEUROSCI.2439-15.2016.
4. Kirkwood, N.K., O’Reilly, M., Derudas, M., Kenyon, E.J., Huckvale, R., Netten, S.M. van, Ward, S.E., Richardson, G.P. & Kros, C.J. (2017). d-Tubocurarine and berbamine: alkaloids that are permeant blockers of the hair cell’s mechano-electrical transducer channel and protect from aminoglycoside toxicity. Frontiers in Cellular Neuroscience 11, 262. doi: 10.3389/fncel.2017.00262.
5. Kenyon, E.J, Kirkwood, N.K., Kitcher, S.R., O’Reilly, M., Derudas, M., Cantillon, D.M., Goodyear, R.J., Secker, A., Baxendale, S., Bull, J.C., Waddell, S.J., Whitfield T.T., Ward, S.E., Kros C.J. & Richardson G.P. (2017). Identification of ion-channel modulators that protect against aminoglycoside-induced hair-cell death. JCI Insight 2, e96773. doi: 10.1172/jci.insight.96773.
6. Kros, C.J. & Steyger, P.S. (2018). Aminoglycoside- and cisplatin-induced ototoxicity: mechanisms and otoprotective strategies. Cold Spring Harbor Perspectives in Medicine a033548. doi: 10.1101/cshperspect.a03354
7. O'Reilly, M., Kirkwood, N.K., Kenyon, E.J., Huckvale, R., Cantillon, D.M., Waddell, S.J., Ward, S.E., Richardson, G.P., Kros, C.J., & Derudas, M. (2019). Design, synthesis, and biological evaluation of a new series of carvedilol derivatives that protect sensory hair cells from aminoglycoside-induced damage by blocking the mechanoelectrical transducer channel. Journal of Medicinal Chemistry 62, 5312-5329. doi: 10.1021/acs.jmedchem.8b01325.
8. Kitcher, S.R., Kirkwood, N.K., Camci, E.D., Wu, P., Gibson, R.M., Redila, V.A., Ogelman, R., Simon, J.A., Rubel, E.W., Raible, D.W., Richardson, G.P. & Kros C.J. (2019). ORC-13661 protects sensory hair cells from aminoglycoside and cisplatin ototoxicity. JCI Insight 4, e126764. doi: 10.1172/jci.insight.126764.