The relationship between the structure and toxicity of aminoglycoside antibiotics

Jospe-Kaufman, Moriah; Siomin, Liza; Fridman, Micha

doi:10.1016/j.bmcl.2020.127218

Cited by 76 publications

(56 citation statements)

References 53 publications

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“…Aminoglycosides suffer several limitations as potential PTC readthrough treatments for rare genetic disorders. At the organismal level, they are known to cause oto-and nephro-toxicity via preferential accumulation and retention in cochlear cells and proximal tubule cells [42][43][44]. At the cellular level, their toxicity has been linked to damage to the lysosomal membrane following uptake by endocytosis and accumulation in this compartment [45][46][47], as well as inhibition of mitochondrial protein synthesis [12,15].…”

Section: Discussionmentioning

confidence: 99%

Small molecule Y-320 stimulates ribosome biogenesis, protein synthesis, and aminoglycoside-induced premature termination codon readthrough

et al. 2021

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Premature termination codons (PTC) cause over 10% of genetic disease cases. Some aminoglycosides that bind to the ribosome decoding center can induce PTC readthrough and restore low levels of full-length functional proteins. However, concomitant inhibition of protein synthesis limits the extent of PTC readthrough that can be achieved by aminoglycosides like G418. Using a cell-based screen, we identified a small molecule, the phenylpyrazoleanilide Y-320, that potently enhances TP53, DMD, and COL17A1 PTC readthrough by G418. Unexpectedly, Y-320 increased cellular protein levels and protein synthesis, measured by SYPRO Ruby protein staining and puromycin labeling, as well as ribosome biogenesis measured using antibodies to rRNA and ribosomal protein S6. Y-320 did not increase the rate of translation elongation and it exerted its effects independently of mTOR signaling. At the single cell level, exposure to Y-320 and G418 increased ribosome content and protein synthesis which correlated strongly with PTC readthrough. As a single agent, Y-320 did not affect translation fidelity measured using a luciferase reporter gene but it enhanced misincorporation by G418. RNA-seq data showed that Y-320 up-regulated the expression of CXC chemokines CXCL10, CXCL8, CXCL2, CXCL11, CXCL3, CXCL1, and CXCL16. Several of these chemokines exert their cellular effects through the receptor CXCR2 and the CXCR2 antagonist SB225002 reduced cellular protein levels and PTC readthrough in cells exposed to Y-320 and G418. These data show that the self-limiting nature of PTC readthrough by G418 can be compensated by Y-320, a potent enhancer of PTC readthrough that increases ribosome biogenesis and protein synthesis. They also support a model whereby increased PTC readthrough is enabled by increased protein synthesis mediated by an autocrine chemokine signaling pathway. The findings also raise the possibility that inflammatory processes affect cellular propensity to readthrough agents and that immunomodulatory drugs like Y-320 might find application in PTC readthrough therapy.

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Section: Discussionmentioning

confidence: 99%

Small molecule Y-320 stimulates ribosome biogenesis, protein synthesis, and aminoglycoside-induced premature termination codon readthrough

et al. 2021

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“…As anticipated on the basis of work by the Wong group in the ribostamycin series, [12] the β‐D‐ribofuranosyl derivative 2 carrying a 3‐ O ‐(2‐aminoethyl) substituent in the ribose ring was more active than the earlier [11] 5‐ O ‐β‐D‐ribofuranosyl derivative and apramycin itself with regards to both the inhibition of the bacterial ribosome (Table 1) and antibacterial activity against wild‐type ESKAPE pathogens (Table 2). However, 2 showed a marked reduction in selectivity for the bacterial over the eukaryotic hybrid ribosomes carrying the human mutant mitochondrial (A1555G) decoding A site [13] (Table 1) indicative of potentially increased ototoxicity [4g,13] . Additionally, the ribofuranosyl moiety of 2 conferred susceptibility to deactivation by the aminoglycoside phosphotransferases (APHs) acting on the ribofuranosyl primary hydroxyl group, the APH(3’,5’’) isozymes [14] .…”

Section: Figurementioning

confidence: 99%

An Advanced Apralog with Increased in vitro and in vivo Activity toward Gram‐negative Pathogens and Reduced ex vivo Cochleotoxicity

et al. 2020

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We describe the convergent synthesis of a 5‐O‐β‐D‐ribofuranosyl‐based apramycin derivative (apralog) that displays significantly improved antibacterial activity over the parent apramycin against wild‐type ESKAPE pathogens. In addition, the new apralog retains excellent antibacterial activity in the presence of the only aminoglycoside modifying enzyme (AAC(3)‐IV) acting on the parent, without incurring susceptibility to the APH(3’) mechanism that disables other 5‐O‐β‐D‐ribofuranosyl 2‐deoxystreptamine type aminoglycosides by phosphorylation at the ribose 5‐position. Consistent with this antibacterial activity, the new apralog has excellent 30 nM activity (IC50) for the inhibition of protein synthesis by the bacterial ribosome in a cell‐free translation assay, while retaining the excellent across‐the‐board selectivity of the parent for inhibition of bacterial over eukaryotic ribosomes. Overall, these characteristics translate into excellent in vivo efficacy against E. coli in a mouse thigh infection model and reduced ototoxicity vis à vis the parent in mouse cochlear explants.

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“…Long term antibiotic use can help to manage biofilm infections, but often fails while also increasing risk of antibiotic resistance and toxic side effects 7 . Furthermore, overuse of aminoglycoside antibiotics can lead to nephrotoxic and ototoxic side effects 8 . Thus, the occurrence of biofilm infections can lead to increased hospital time and trauma for patients, as well as increased cost of care.…”

Section: Introductionmentioning

confidence: 99%

In vitro evaluation of loaded chitosan membranes for pain relief and infection prevention

et al. 2021

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Wounds resulting from surgeries, implantation of medical devices, and musculoskeletal trauma result in pain and can also result in infection of damaged tissue. Up to 80% of these infections are due to biofilm formation either on the surface of implanted devices or on surrounding wounded tissue. Bacteria within a biofilm have intrinsic growth and development characteristics that allow them to withstand up to 1,000 times the minimum inhibitory concentration of antibiotics, demonstrating the need for new therapeutics to prevent and treat these infections. Cis‐2‐decenoic acid (C2DA) is known to disperse preformed biofilms and can prevent biofilm formation entirely for some strains of bacteria. Additionally, local anesthetics like bupivacaine have been shown to have antimicrobial effects against multiple bacterial strains. This study sought to evaluate hexanoic acid‐treated electrospun chitosan membranes (HA‐ESCM) as wound dressings that release C2DA and bupivacaine to simultaneously prevent infection and alleviate pain associated with musculoskeletal trauma. Release profiles of both therapeutics were evaluated, and membranes were tested in vitro against Methicillin‐resistant Staphylococcus aureus (MRSA) to determine efficacy in preventing biofilm infection and bacterial growth. Results indicate that membranes release both therapeutics for 72 hr, and release profile can be tailored by loading concentration. Membranes were effective in preventing biofilm growth but were toxic to fibroblasts when loaded with 2.5 or 5 mg of bupivacaine.

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The relationship between the structure and toxicity of aminoglycoside antibiotics

Cited by 76 publications

References 53 publications

Small molecule Y-320 stimulates ribosome biogenesis, protein synthesis, and aminoglycoside-induced premature termination codon readthrough

Small molecule Y-320 stimulates ribosome biogenesis, protein synthesis, and aminoglycoside-induced premature termination codon readthrough

An Advanced Apralog with Increased in vitro and in vivo Activity toward Gram‐negative Pathogens and Reduced ex vivo Cochleotoxicity

In vitro evaluation of loaded chitosan membranes for pain relief and infection prevention

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