What they found
TL;DR (qwen3.6:35b): Researchers identified compound 28510, a novel non-MET-mediated otoprotective agent that effectively prevents aminoglycoside-induced hair cell damage in zebrafish without interfering with the drug’s antibacterial activity. This compound demonstrates broad efficacy against multiple aminoglycosides and favorable drug-like properties, establishing it as a promising lead for preventing antibiotic-related hearing loss.
Aminoglycoside (AG) antibiotics are indispensable for treating severe infections but frequently cause irreversible hearing loss, with no approved preventive therapies. Using in vivo zebrafish lateral line screening combined with computational scaffold-hopping, we identified a novel class of otoprotective compounds. Starting from the ion channel modulator MR16728, we discovered compound 28510 as a potent lead compound. Compound 28510 provided robust, dose-dependent protection against AG-induced hair cell damage, restoring neuromast hair cell integrity to near-control levels in acute assays and demonstrating broad efficacy across clinically relevant AGs (gentamicin, tobramycin, amikacin, streptomycin) in chronic exposures. Importantly, 28510 exhibited a favorable therapeutic window, with low micromolar 50% hair cell protection concentration (HC50) values consistently below toxicity thresholds. Mechanistically, FM1-43 and Texas Red-conjugated gentamicin uptake assays revealed that 28510 does not inhibit mechanotransduction (MET) channel-mediated AG entry, distinguishing it from current clinical candidates and pointing to a novel intracellular protective mechanism. 28510 preserved AG antibacterial activity in E. coli assays, supporting its translational compatibility as a co-therapeutic agent. Combinations of 28510 with related analogs did not yield synergistic protection; 28510 alone remained the most effective compound. In silico absorption, distribution, metabolism, and excretion (ADME) predictions further confirmed its highly favorable drug-like properties, including excellent intestinal and oral absorption. Together, these findings establish 28510 as a first-in-class, non-MET-mediated otoprotective lead with broad efficacy and a favorable therapeutic profile, highlighting a new strategy for preventing AG-induced hearing loss.
How this applies to our program
This research is relevant to the STRC/DFNB16 program as it explores alternative, non-MET-mediated mechanisms for hair cell protection, which could complement or inform strategies for preserving hair cell integrity in genetic deafness contexts. The identification of a novel intracellular protective pathway offers potential new targets for therapeutic intervention beyond the mechanotransduction channel.
Key numbers
- Compound 28510 restored neuromast hair cell integrity to near-control levels in acute assays
- Effective against four clinically relevant aminoglycosides: gentamicin, tobramycin, amikacin, and streptomycin
- Low micromolar 50% hair cell protection concentration (HC50) values consistently below toxicity thresholds
Links
- biorxiv_id: https://www.biorxiv.org/content/10.64898/2026.05.14.725303
- DOI: https://doi.org/10.64898/2026.05.14.725303
Connections
[source]auto-indexed 2026-05-20 by strc-lit-watch