Dissociating antibacterial from ototoxic effects of gentamicin C-subtypes

Abstract

Gentamicin is a potent broad-spectrum aminoglycoside antibiotic whose use is hampered by ototoxic side-effects. Hospital gentamicin is a mixture of five gentamicin C-subtypes and several impurities of various ranges of nonexact concentrations. We developed a purification strategy enabling assaying of individual C-subtypes and impurities for ototoxicity and antimicrobial activity. We found that C-subtypes displayed broad and potent in vitro antimicrobial activities comparable to the hospital gentamicin mixture. In contrast, they showed different degrees of ototoxicity in cochlear explants, with gentamicin C2b being the least and gentamicin C2 the most ototoxic. Structure–activity relationships identified sites in the C4′-C6′ region on ring I that reduced ototoxicity while preserving antimicrobial activity, thus identifying targets for future drug design and mechanisms for hair cell toxicity. Structure–activity relationship data suggested and electrophysiological data showed that the C-subtypes both bind and permeate the hair cell mechanotransducer channel, with the stronger the binding the less ototoxic the compound. Finally, both individual and reformulated mixtures of C-subtypes demonstrated decreased ototoxicity while maintaining antimicrobial activity, thereby serving as a proof-of-concept of drug reformulation to minimizing ototoxicity of gentamicin in patients.

Mechanism and Prevention of Ototoxicity Induced by Aminoglycosides

“…At the same time, new alternative drugs can be developed to reduce ototoxicity. Recent studies have purified hospital gentamicin, and analyzed the ototoxicity and antimicrobial activity of individual C-subtypes and impurities, providing ideas for the design of future drugs (O'Sullivan et al, 2020 ).…”

In-Depth Study of Thymus vulgaris Essential Oil: Towards Understanding the Antibacterial Target Mechanism and Toxicological and Pharmacological Aspects

“…As represented in Table 2 , TVEO displayed an interesting antibacterial activity against the four tested bacterial strains with inhibition zones ranging from of 21 to 23 mm against Gram-negative and Gram-positive bacteria, respectively. In addition, it is important to note that monoterpenes exhibit a broad-spectrum antibacterial activity against pathogenic bacteria [ 92 , 93 ]. This fact could be explained by the presence of a lipophilic character which provides to monoterpenes the ability to adhere to bacterial cell membrane lipids and to deploy their antibacterial action [ 94 ].…”

In vivo real-time imaging reveals megalin as the aminoglycoside gentamicin transporter into cochlea whose inhibition is otoprotective

“…At first take, it is surprising that there is no change in ABR response during the uptake of GTTR when the GTTR would be predicted to block the MET channel. However, the hair bundle membrane potential is quite negative due to the endocochlear potential, endolymph has a very low Ca 2+ concentration, and the amount of GTTR entering the endolymph is quite low; each of these factors likely leads to an alleviation of the channel block and promotion of permeation through the MET channel ( 29 , 65 , 66 ). Thus, if the channel is not blocked, ABRs will be unaffected.…”