Aminoglycosides are a widely used class of antibacterials renowned for their effectiveness and broad antimicrobial spectrum.However,their use leads to irreversible hearing damage by causing apoptosis of hair cells as their direct target.In addition,the hearing damage caused by aminoglycosides involves damage of spiral ganglion neurons upon exposure.To investigate the mechanisms underlying spiral ganglion neuron degeneration induced by aminoglycosides,we used a C57BL/6J mouse model treated with kanamycin.We found that the mice exhibited auditory deficits following the acute loss of outer hair cells.Spiral ganglion neurons displayed hallmarks of pyroptosis and exhibited progressive degeneration over time.Transcriptomic profiling of these neurons showed significant upregulation of genes associated with inflammation and immune response,particularly those related to the NLRP3 inflammasome.Activation of the canonical pyroptotic pathway in spiral ganglion neurons was observed,accompanied by infiltration of macrophages and the release of proinflammatory cytokines.Pharmacological intervention targeting NLRP3 using Mcc950 and genetic intervention using NLRP3 knockout ameliorated spiral ganglion neuron degeneration in the injury model.These findings suggest that NLRP3 inflammasome-mediated pyroptosis plays a role in aminoglycoside-induced spiral ganglion neuron degeneration.Inhibition of this pathway may offer a potential therapeutic strategy for treating sensorineural hearing loss by reducing spiral ganglion neuron degeneration.
Aminoglycosides(AGs)are a class of antibiotics with a broad spectrum of activity.However,their use is limited by safety concerns associated with nephrotoxicity and ototoxicity,as well as drug resistance.To address these issues,semi-synthetic approaches for modifying natural AGs have generated new generations of AGs,however,with limited types of modification due to significant challenges in synthesis.This study explores a novel approach that harness the bacterial biosynthetic machinery of gentamicins and kanamycins to create hybrid AGs.This was achieved by glycodiversification of gentamicins via swapping the glycosyltransferase(GT)in their producer with the GT from kanamycins biosynthetic pathway and resulted in the creation of a series of novel AGs,therefore referred to as genkamicins(GKs).The manipulation of the hybrid biosynthetic pathway enabled the targeted accumulation of different GK species and the isolation and characterization of six GK components.These compounds display retained antimicrobial activity against a panel of World Health Organization(WHO)critical priority pathogens,and GK-C2a,in particular,demonstrates low ototoxicity compared to clinical drugs in zebrafish embryos.This study provides a new strategy for diversifying the structure of AGs and a potential avenue for developing less toxic AG drugs to combat infectious diseases.
