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Kanani, Alhamdouni, Hachim, and Azzawi: Identification of off-target effects of aminoglycosides on human genes

Introduction: All medically useful antibiotics should have the potential to distinguish between target microbes (bacteria) and host cells. Prolonged antibiotic treatment can lead to detrimental side-effects in patients, but the mechanisms underlying the effects of antibiotics in mammalian systems remain unclear. Understanding the molecular mechanisms of toxicity may aid in the design of adjunctive therapies to improve antibiotic tolerance.

Aim and objective: The study aimed to characterize the mechanistic effects of clinically relevant bactericidal antibiotics on mammalian cells using publicly available data. Owing to the relatively frequent occurrence of nephrotoxicity and ototoxicity during aminoglycoside treatment, this study focused on this antibiotic group.

Materials and method: Aminoglycosides (amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin and spectinomycin) were investigated for their effect on human genomes using the Comparative Toxicogenomics Database public website and research tool. For each drug, the drug–gene interactions were listed as either increased or decreased gene expression. The functions of those genes listed were searched using the GeneDecks (www.genecards.org) online tool.

Results: Aminoglycosides were found to increase the expression of 1573 genes involved in mortality/ageing, cellular, immune system, and homeostasis/metabolism phenotypes. On the other hand, aminoglycosides decreased the expression of another 666 genes involved in in mortality/ageing, homeostasis/metabolism, cellular, growth/size, nervous system, and behaviour/neurological phenotypes. Beside these physiological pathways, aminoglycosides affected genes known to be involved in certain diseases such as neuronitis, breast cancer, prostatitis, endotheliitis, pancreatitis, leukaemia, hepatitis, prostate cancer, lung cancer, adenocarcinoma and hepatocellular carcinoma.

Conclusion: Aminoglycosides have numerous off-target effects on human genomes by affecting the expression of genes involved in major cellular phenotypes and clinical conditions that may explain the clinically documented side-effects of prolonged use of such drugs. Confirming these observations using in vitro and in vivo models, such as cell lines and animal models, is recommended.





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