Toxicity of aminoglycoside antibiotics may be due to alternate binding of the human mitochondrial ribosomal RNA

Hong, Seoyeon; Fanning, Kathryn D.; Harris, K S; Frohlich, Kyla M.; Agris, Paul F.

doi:10.1096/fasebj.29.1_supplement.575.20

Cited by 2 publications

(2 citation statements)

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“…Therefore, when developing novel AGs, it is crucial that (i) they be highly selective for the bacterial A-site over the human A-site counterpart, as mutations in human mitochondrial ribosomes that result in higher affinity for these ligands often lead to drug toxicity, 11,12 and (ii) they evade the action of the AMEs responsible for the majority of resistance to these drugs. In this work, we have combined the two aforementioned molecular design strategies in order to produce novel compounds that are both poor substrates for AMEs and display increased affinities for their RNA targets over their unmodified parent AG.…”

Section: Introductionmentioning

confidence: 99%

Arginine-linked neomycin B dimers: synthesis, rRNA binding, and resistance enzyme activity

et al. 2016

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The nucleotides comprising the ribosomal decoding center are highly conserved, as they are important for maintaining translational fidelity. The bacterial A-site has a small base variation as compared with the human analogue, allowing aminoglycoside (AG) antibiotics to selectively bind within this region of the ribosome and negatively affect microbial protein synthesis. Here, by using a fluorescence displacement screening assay, we demonstrate that neomycin B (NEO) dimers connected by L-arginine-containing linkers of varying length and composition bind with higher affinity to model A-site RNAs compared to NEO, with IC50 values ranging from ~40–70 nM, and that a certain range of linker lengths demonstrates a clear preference for the bacterial A-site RNA over the human analogue. Furthermore, AG-modifying enzymes (AMEs), such as AG O-phosphotransferases, which are responsible for conferring antibiotic resistance in many types of infectious bacteria, demonstrate markedly reduced activity against several of the L-arginine-linked NEO dimers in vitro. The antimicrobial activity of these dimers against several bacterial strains is weaker than that of the parent NEO.

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Section: Introductionmentioning

confidence: 99%

Arginine-linked neomycin B dimers: synthesis, rRNA binding, and resistance enzyme activity

et al. 2016

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“…Several classes of antibiotics, despite their clinical effectiveness, have been shown to lead to severe mitochondrial dysfunction in eukaryotes [1][2][3]. The mechanism by which antibiotics damage mitochondria in the host is the impairment of conserved biochemical processes originating from bacterial progenitors [4,5].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Side Effects of Surgical Prophylactic Antibiotics Ceftriaxone and Rifaximin Lead to Bowel Mucosal Damage

Baráth

Jász

Horváth

et al. 2022

IJMS

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Despite their clinical effectiveness, a growing body of evidence has shown that many classes of antibiotics lead to mitochondrial dysfunction. Ceftriaxone and Rifaximin are first choice perioperative antibiotics in gastrointestinal surgery targeting fundamental processes of intestinal bacteria; however, may also have negative consequences for the host cells. In this study, we investigated their direct effect on mitochondrial functions in vitro, together with their impact on ileum, colon and liver tissue. Additionally, their impact on the gastrointestinal microbiome was studied in vivo, in a rat model. Rifaximin significantly impaired the oxidative phosphorylation capacity (OxPhos) and leak respiration in the ileal mucosa, in line with increased oxidative tissue damage and histological changes following treatment. Ceftriaxone prophylaxis led to similar changes in the colon mucosa. The composition and diversity of bacterial communities differed extensively in response to antibiotic pre-treatment. However, the relative abundances of the toxin producing species were not increased. We have confirmed the harmful effects of prophylactic doses of Rifaximin and Ceftriaxone on the intestinal mucosa and that these effects were related to the mitochondrial dysfunction. These experiments raise awareness of mitochondrial side effects of these antibiotics that may be of clinical importance when evaluating their adverse effects on bowel mucosa.

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Toxicity of aminoglycoside antibiotics may be due to alternate binding of the human mitochondrial ribosomal RNA

Cited by 2 publications

References 1 publication

Arginine-linked neomycin B dimers: synthesis, rRNA binding, and resistance enzyme activity

Arginine-linked neomycin B dimers: synthesis, rRNA binding, and resistance enzyme activity

Mitochondrial Side Effects of Surgical Prophylactic Antibiotics Ceftriaxone and Rifaximin Lead to Bowel Mucosal Damage

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