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This study highlights the significance of the Ullmann coupling reaction in modern organic synthesis and advances catalytic methodologies through the introduction of a kanamycin−copper complex as a highly efficient catalyst for the synthesis of diverse N−aryl compounds. We demonstrate the catalyst's versatility by synthesizing 20 diaryl−amine instances, 21 Ar(het)−N compounds, and 10 miscellaneous examples. NMR, IR, and UV spectroscopy offer insights into the catalyst's behaviour. Additionally, DFT studies support the catalyst's proficiency in generating SO4−⋅ radicals by stabilizing with amino sugar moieties. Ex‐situ NMR experiments confirm a ternary complex‐based mechanism at concentrations below 0.1 μM. Furthermore, we showcase the degradation of methylene blue to its precursor amine under optimized conditions. Overall, this research underscores the potential of Ullmann condensation reactions in contemporary organic synthesis and contributes significantly to the advancement of catalytic methodologies. [ABSTRACT FROM AUTHOR]

AbstractWe analyzed the efficacy and safety of aminoglycosides in a retrospective study of 415 patients with acute appendicitis and 277 patients with acute cholecystitis. The following variables increased the incidence of postoperative complications, defined as surgical site infection, recurrent intraabdominal infection, non-infectious post-operative complication, or death: age (p = 0.016 and 0.011), kidney disease (p = 0.019 and <0.001), and ASA Score (p < 0.001). The type of antibiotic therapy did not have a statistically significant effect on the incidence of postoperative complications in patients with acute appendicitis and cholecystitis (p = 0.561 and 0.547, respectively). A linear regression model showed a higher complication rate in patients with kidney disease (p = 0.014) and neoplasms (p = 0.013); the type of antibiotic therapy did not have a significant effect on the outcome (p = 0.765). There was no statistically significant difference in the post-treatment levels of creatinine in patients treated with aminoglycosides (gentamicin 3 mg/kg once daily) and in those who received other antibiotics (p = 0.75). [ABSTRACT FROM AUTHOR]

Background: Aminoglycosides have been a cornerstone of the treatment of nosocomial infections caused by Pseudomonas aeruginosa for over 80 years. However, escalating emergence of resistance poses a significant challenge. Therefore, this study aimed to investigate the prevailing patterns of aminoglycoside resistance among clinical isolates of P. aeruginosa in Iran; as well as the underlying resistance mechanisms observed in patients referred to Ardabil hospitals. Methods: A total of 200 isolates from five hospitals were evaluated. The resistance profiles of P. aeruginosa isolates to tobramycin, amikacin, and netilmicin were determined using the disk diffusion method. The capacity of aminoglycoside-resistant isolates to form biofilms was assessed through a phenotypic assay, and the results were confirmed using the gene amplification technique. The presence of genes associated with aminoglycoside resistance was detected using polymerase chain reaction (PCR). Quantitative reverse transcription PCR (qRT-PCR) was performed to measure the expression levels of genes encoding the MexXY-OprM efflux pump and PhoPQ two-component system (TCS). Results: The prevalence of aminoglycoside-resistant P. aeruginosa isolates was 48%, with 94.7% demonstrating multidrug resistance (MDR). All aminoglycoside-resistant P. aeruginosa strains exhibited biofilm-forming capabilities and harbored all the genes associated with biofilm production. Among the nine genes encoding 16S rRNA methylase and aminoglycoside-modifying enzymes, three genes were detected in these isolates: aac(6')-Ib (85.4%), ant(2")-Ia (18.7%), and aph(3')-VI (3.1%). Additionally, all aminoglycoside-resistant P. aeruginosa isolates carried mexY and phoP genes, although the expression levels of mexY and phoP were 75% and 87.5%, respectively. Conclusion: Given the considerably high prevalence of aminoglycoside-resistant P. aeruginosa strains, urgent measures are warranted to transition towards the use of novel aminoglycosides and to uphold vigilant surveillance of resistance patterns. [ABSTRACT FROM AUTHOR]

Abstract Background Aminoglycosides have been a cornerstone of the treatment of nosocomial infections caused by Pseudomonas aeruginosa for over 80 years. However, escalating emergence of resistance poses a significant challenge. Therefore, this study aimed to investigate the prevailing patterns of aminoglycoside resistance among clinical isolates of P. aeruginosa in Iran; as well as the underlying resistance mechanisms observed in patients referred to Ardabil hospitals. Methods A total of 200 isolates from five hospitals were evaluated. The resistance profiles of P. aeruginosa isolates to tobramycin, amikacin, and netilmicin were determined using the disk diffusion method. The capacity of aminoglycoside-resistant isolates to form biofilms was assessed through a phenotypic assay, and the results were confirmed using the gene amplification technique. The presence of genes associated with aminoglycoside resistance was detected using polymerase chain reaction (PCR). Quantitative reverse transcription PCR (qRT-PCR) was performed to measure the expression levels of genes encoding the MexXY-OprM efflux pump and PhoPQ two-component system (TCS). Results The prevalence of aminoglycoside-resistant P. aeruginosa isolates was 48%, with 94.7% demonstrating multidrug resistance (MDR). All aminoglycoside-resistant P. aeruginosa strains exhibited biofilm-forming capabilities and harbored all the genes associated with biofilm production. Among the nine genes encoding 16S rRNA methylase and aminoglycoside-modifying enzymes, three genes were detected in these isolates: aac(6’)-Ib (85.4%), ant(2’’)-Ia (18.7%), and aph(3’)-VI (3.1%). Additionally, all aminoglycoside-resistant P. aeruginosa isolates carried mexY and phoP genes, although the expression levels of mexY and phoP were 75% and 87.5%, respectively. Conclusion Given the considerably high prevalence of aminoglycoside-resistant P. aeruginosa strains, urgent measures are warranted to transition towards the use of novel aminoglycosides and to uphold vigilant surveillance of resistance patterns.

Abstract Background Ototoxicity is a major side effect of many broadly used aminoglycoside antibiotics (AGs) and no FDA-approved otoprotective drug is available currently. The zebrafish has recently become a valuable model to investigate AG-induced hair cell toxicity and an expanding list of otoprotective compounds that block the uptake of AGs have been identified from zebrafish-based screening; however, it remains to be established whether inhibiting intracellular cell death pathway(s) constitutes an effective strategy to protect against AG-induced ototoxicity. Results We used the zebrafish model as well as in vitro cell-based assays to investigate AG-induced cell death and found that ferroptosis is the dominant type of cell death induced by neomycin. Neomycin stimulates lipid reactive oxygen species (ROS) accumulation through mitochondrial pathway and blocking mitochondrial ferroptosis pathway effectively protects neomycin-induced cell death. We screened an alkaloid natural compound library and identified seven small compounds that protect neomycin-induced ototoxicity by targeting ferroptosis pathway: six of them are radical-trapping agents (RTAs) while the other one (ellipticine) regulates intracellular iron homeostasis, which is essential for the generation of lipid ROS to stimulate ferroptosis. Conclusions Our study demonstrates that blocking intracellular ferroptosis pathway is an alternative strategy to ameliorate neomycin-induced ototoxicity and provides multiple hit compounds for further otoprotective drug development.

Abstract Background Pharmacokinetics of amikacin administered IV to neonatal foals are described, but little data are available regarding the plasma concentrations contributed by concurrent intra‐articular (IA) administration. Hypothesis/Objectives Compare the pharmacokinetics of amikacin when the total dose is administered IV compared to being divided between IV and IA routes of administration in neonatal foals and predict the plasma concentrations from various combined IV and IA dosing regimens. Animals Eight healthy neonatal foals. Methods Foals received 3 amikacin treatment protocols: (1) IV‐only (25 mg/kg q24h IV), (2) concurrent IV and IA (16.7 mg/kg q24h IV and 8.3 mg/kg q24h into 1 tarsocrural joint), and (3) IA‐only (8.3 mg/kg q24h into 1 tarsocrural joint). Protocols were administered for 3 days beginning at 7, 14, and 21 days of age. Plasma concentrations ≥53 μg/mL at 30 minutes were considered therapeutic for isolates with intermediate susceptibility. Results Foal age was a significant variable. The IV‐only protocol met or exceeded the 30‐minute plasma concentrations considered therapeutic (mean μg/mL [95% confidence interval, CI]) in 7‐ to 9‐day‐old (54.0 [52.2‐56.9]), 14‐ to 16‐day‐old (58.1 [55.2‐61.0]), and 21‐ to 23‐day‐old (66.6 [63.7‐69.6]) foals. Concurrent IV and IA protocol did not reach the 30‐minute concentration considered therapeutic in 7‐ to 9‐day‐old foals (46.5 [43.6‐49.4]) but did in 14‐ to 16‐day‐old (62.9 [60.0‐65.8]) and 21‐to 23‐day‐old (62.6 [59.7‐65.6]) foals. Conclusions and Clinical Importance Concurrent IV and IA administration of amikacin produces 30‐minute plasma concentrations considered therapeutic in foals 14 to 23 days old, but concentrations observed in younger foals might be below those considered therapeutic for isolates with intermediate susceptibility to amikacin.

Background: Ototoxicity is a major side effect of many broadly used aminoglycoside antibiotics (AGs) and no FDA-approved otoprotective drug is available currently. The zebrafish has recently become a valuable model to investigate AG-induced hair cell toxicity and an expanding list of otoprotective compounds that block the uptake of AGs have been identified from zebrafish-based screening; however, it remains to be established whether inhibiting intracellular cell death pathway(s) constitutes an effective strategy to protect against AG-induced ototoxicity. Results: We used the zebrafish model as well as in vitro cell-based assays to investigate AG-induced cell death and found that ferroptosis is the dominant type of cell death induced by neomycin. Neomycin stimulates lipid reactive oxygen species (ROS) accumulation through mitochondrial pathway and blocking mitochondrial ferroptosis pathway effectively protects neomycin-induced cell death. We screened an alkaloid natural compound library and identified seven small compounds that protect neomycin-induced ototoxicity by targeting ferroptosis pathway: six of them are radical-trapping agents (RTAs) while the other one (ellipticine) regulates intracellular iron homeostasis, which is essential for the generation of lipid ROS to stimulate ferroptosis. Conclusions: Our study demonstrates that blocking intracellular ferroptosis pathway is an alternative strategy to ameliorate neomycin-induced ototoxicity and provides multiple hit compounds for further otoprotective drug development. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the application of aminoglycoside anti-infective drugs in inpatients, so as to promote rational drug use in clinic. METHODS: Demographic data, drug administration, pathogen examination, drug combination, and adverse drug reactions of inpatients with systemic aminoglycosides anti-infective drugs in the hospital from Jan. 1st to Jun. 1st, 2023 were retrospectively analyzed. RESULTS: A total of 360 inpatients were treated with amikacin, etimicin, and gentamicin during this period. There were 251 male patients and 109 female patients with an average age of (60. 39±18. 11) years. Aminoglycoside anti-infective drugs were mainly used in the treatment of Gram-negative bacterial infection, and were mostly combined with β-lactam drugs. Among 202 patients treated with medication, the effective rate was 91. 09% ( 184 / 202). Serum creatinine of 25 patients increased significantly after treatment (6. 94%). Totally 133 patients had irrational medication, including 24 cases of irrational dosage (18. 05%), 39 cases of improper drug combination (29. 32%), 52 cases of irrational prophylactic medication regimen (39. 10%), 25 cases of irrational timing of perioperative medication (18. 80%), and 12 cases of irrational selection of prophylactic medication ( 9. 02%). CONCLUSIONS: The clinical application of aminoglycoside antiinfective drugs in the hospital is generally rational, yet there are still some problems such as inaccurate dosage and irrational drug combination. Rational medication should be guided by therapeutic drug monitoring, and the changes of related indicators of renal function should be paid close attention during drug use. [ABSTRACT FROM AUTHOR]

Aminoglycosides are commonly used antibiotics for treatment of gram-negative bacterial infections, however, they might act on inner ear, leading to hair-cell death and hearing loss. Currently, there is no targeted therapy for aminoglycoside ototoxicity, since the underlying mechanisms of aminoglycoside-induced hearing impairments are not fully defined. This study aimed to investigate whether the calcium channel blocker verapamil and changes in intracellular & extracellular calcium could ameliorate aminoglycoside-induced ototoxicity in zebrafish. The present findings showed that a significant decreased number of neuromasts in the lateral lines of zebrafish larvae at 5 days' post fertilization after neomycin (20 μM) and gentamicin (20 mg/mL) exposure, which was prevented by verapamil. Moreover, verapamil (10–100 μM) attenuated aminoglycoside-induced toxic response in different external calcium concentrations (33–3300 μM). The increasing extracellular calcium reduced hair cell loss from aminoglycoside exposure, while lower calcium facilitated hair cell death. In contrast, calcium channel activator Bay K8644 (20 μM) enhanced aminoglycoside-induced ototoxicity and reversed the protective action of higher external calcium on hair cell loss. However, neomycin-elicited hair cell death was not altered by caffeine, ryanodine receptor (RyR) agonist, and RyR antagonists, including thapsigargin, ryanodine, and ruthenium red. The uptake of neomycin into hair cells was attenuated by verapamil and under high external calcium concentration. Consistently, the production of reactive oxygen species (ROS) in neuromasts exposed to neomycin was also reduced by verapamil and high external calcium. Significantly, zebrafish larvae when exposed to neomycin exhibited decreased swimming distances in reaction to droplet stimulus when compared to the control group. Verapamil and elevated external calcium effectively protected the impaired swimming ability of zebrafish larvae induced by neomycin. These data imply that prevention of hair cell damage correlated with swimming behavior against aminoglycoside ototoxicity by verapamil and higher external calcium might be associated with inhibition of excessive ROS production and aminoglycoside uptake through cation channels. These findings indicate that calcium channel blocker and higher external calcium could be applied to protect aminoglycoside-induced listening impairments. [ABSTRACT FROM AUTHOR]

Rett syndrome (RTT) is a neurodevelopmental disorder resulting from genetic mutations in the methyl CpG binding protein 2 (MeCP2) gene. Specifically, around 35% of RTT patients harbor premature termination codons (PTCs) within the MeCP2 gene due to nonsense mutations. A promising therapeutic avenue for these individuals involves the use of aminoglycosides, which stimulate translational readthrough (TR) by causing stop codons to be interpreted as sense codons. However, the effectiveness of this treatment depends on several factors, including the type of stop codon and the surrounding nucleotides, collectively referred to as the stop codon context (SCC). Here, we develop a high-content reporter system to precisely measure TR efficiency at different SCCs, assess the recovery of the full-length MeCP2 protein, and evaluate its subcellular localization. We have conducted a comprehensive investigation into the intricate relationship between SCC characteristics and TR induction, examining a total of 14 pathogenic MeCP2 nonsense mutations with the aim to advance the prospects of personalized therapy for individuals with RTT. Our results demonstrate that TR induction can successfully restore full-length MeCP2 protein, albeit to varying degrees, contingent upon the SCC and the specific position of the PTC within the MeCP2 mRNA. TR induction can lead to the re-establishment of nuclear localization of MeCP2, indicating the potential restoration of protein functionality. In summary, our findings underscore the significance of SCC-specific approaches in the development of tailored therapies for RTT. By unraveling the relationship between SCC and TR therapy, we pave the way for personalized, individualized treatment strategies that hold promise for improving the lives of individuals affected by this debilitating neurodevelopmental disorder. Key messages: The efficiency of readthrough induction at MeCP2 premature termination codons strongly depends on the stop codon context. The position of the premature termination codon on the transcript influences the readthrough inducibility. A new high-content dual reporter assay facilitates the measurement and prediction of readthrough efficiency of specific nucleotide stop contexts. Readthrough induction results in the recovery of full-length MeCP2 and its re-localization to the nucleus. MeCP2 requires only one of its annotated nuclear localization signals. [ABSTRACT FROM AUTHOR]

Background: Pharmacokinetics of amikacin administered IV to neonatal foals are described, but little data are available regarding the plasma concentrations contributed by concurrent intra‐articular (IA) administration. Hypothesis/Objectives: Compare the pharmacokinetics of amikacin when the total dose is administered IV compared to being divided between IV and IA routes of administration in neonatal foals and predict the plasma concentrations from various combined IV and IA dosing regimens. Animals: Eight healthy neonatal foals. Methods: Foals received 3 amikacin treatment protocols: (1) IV‐only (25 mg/kg q24h IV), (2) concurrent IV and IA (16.7 mg/kg q24h IV and 8.3 mg/kg q24h into 1 tarsocrural joint), and (3) IA‐only (8.3 mg/kg q24h into 1 tarsocrural joint). Protocols were administered for 3 days beginning at 7, 14, and 21 days of age. Plasma concentrations ≥53 μg/mL at 30 minutes were considered therapeutic for isolates with intermediate susceptibility. Results: Foal age was a significant variable. The IV‐only protocol met or exceeded the 30‐minute plasma concentrations considered therapeutic (mean μg/mL [95% confidence interval, CI]) in 7‐ to 9‐day‐old (54.0 [52.2‐56.9]), 14‐ to 16‐day‐old (58.1 [55.2‐61.0]), and 21‐ to 23‐day‐old (66.6 [63.7‐69.6]) foals. Concurrent IV and IA protocol did not reach the 30‐minute concentration considered therapeutic in 7‐ to 9‐day‐old foals (46.5 [43.6‐49.4]) but did in 14‐ to 16‐day‐old (62.9 [60.0‐65.8]) and 21‐to 23‐day‐old (62.6 [59.7‐65.6]) foals. Conclusions and Clinical Importance: Concurrent IV and IA administration of amikacin produces 30‐minute plasma concentrations considered therapeutic in foals 14 to 23 days old, but concentrations observed in younger foals might be below those considered therapeutic for isolates with intermediate susceptibility to amikacin. [ABSTRACT FROM AUTHOR]

Aminoglycoside antibiotics target ribosomes and are effective against a wide range of bacteria. Here, we demonstrated that knockout strains related to energy metabolism in Escherichia coli showed increased tolerance to aminoglycosides during the mid-exponential growth phase. Contrary to expectations, these mutations did not reduce the proton motive force or aminoglycoside uptake, as there were no significant changes in metabolic indicators or intracellular gentamicin levels between wild-type and mutant strains. Our comprehensive proteomics analysis unveiled a noteworthy upregulation of proteins linked to the tricarboxylic acid (TCA) cycle in the mutant strains during the mid-exponential growth phase, suggesting that these strains compensate for the perturbation in their energy metabolism by increasing TCA cycle activity to maintain their membrane potential and ATP levels. Furthermore, our pathway enrichment analysis shed light on local network clusters displaying downregulation across all mutant strains, which were associated with both large and small ribosomal binding proteins, ribosome biogenesis, translation factor activity, and the biosynthesis of ribonucleoside monophosphates. These findings offer a plausible explanation for the observed tolerance of aminoglycosides in the mutant strains. Altogether, this research provides valuable insights into the mechanisms of aminoglycoside tolerance, paving the way for novel strategies to combat such cells.

The occurrence of multidrug-resistant Acinetobacter baumannii (MDRA) has increased rapidly and is associated with severe nosocomial infections. MDRA has emerged in the hospital setting and has evolved into extensively drug-resistant A. baumannii (XDRA). A clinical XDRA isolate obtained from a hospitalised patient in 2016 was evaluated for antibiotic susceptibility and whole-genome sequence. The XDRA isolate was resistant to β-lactams, including broad-spectrum cephalosporins and carbapenems, and to aminoglycosides, fosfomycin, fluoroquinolones, tetracyclines, tigecycline, and trimethoprim-sulfamethoxazole. The isolate harboured abaF, ant(3″)-II-c, aph(3″)-Ib, aph(6)-Id, armA, blaADC-73, blaTEM-1, blaOXA-66, blaOXA-23, mphE, msrE and tet(B). Quinolone resistance was associated with mutations gyrA S81L and parC S84L. Tigecycline resistance was associated with a mutation in adeS. The isolate belonged to Oxford and Pasteur scheme sequence type 1050 and 2, respectively, and harboured a conjugative plasmid containing the aminoglycoside resistance transposon TnaphA6. Our study demonstrates that the isolate is closely related to a recent MDRA identified in Australia and the USA, in which a similar conjugative plasmid is not observed. Although the MDRA in Australia caused an outbreak, our hospital's surveillance protocol managed to prevent a further outbreak. Our finding suggests that this XDRA isolate is of concern in hospital and community care settings. The gpi allele could be a marker for discriminating this isolate from clonal complex 92 isolates.

Abstract Background Sensorineural hearing loss (SNHL) poses a major threat to both physical and mental health; however, there is still a lack of effective drugs to treat the disease. Recently, novel biological therapies, such as mesenchymal stem cells (MSCs) and their products, namely, exosomes, are showing promising therapeutic potential due to their low immunogenicity, few ethical concerns, and easy accessibility. Nevertheless, the precise mechanisms underlying the therapeutic effects of MSC-derived exosomes remain unclear. Results Exosomes derived from MSCs reduced hearing and hair cell loss caused by neomycin-induced damage in models in vivo and in vitro. In addition, MSC-derived exosomes modulated autophagy in hair cells to exert a protective effect. Mechanistically, exogenously administered exosomes were internalized by hair cells and subsequently upregulated endocytic gene expression and endosome formation, ultimately leading to autophagy activation. This increased autophagic activity promoted cell survival, decreased the mitochondrial oxidative stress level and the apoptosis rate in hair cells, and ameliorated neomycin-induced ototoxicity. Conclusions In summary, our findings reveal the otoprotective capacity of exogenous exosome-mediated autophagy activation in hair cells in an endocytosis-dependent manner, suggesting possibilities for deafness treatment.

The issue of bacterial resistance has become a matter of significant concern globally, prompting extensive research into the development and clinical application of aminoglycoside antibiotics (AGAs) as a crucial antibacterial therapy. One of the primary mechanisms contributing to aminoglycoside antibiotic resistance is the action of aminoglycoside modifying enzymes (AMEs), which modify aminoglycoside antibiotics and consequently confer drug resistance. Chemical modification of the AME action site can eliminate functional groups vulnerable to AMEs, thus improving drug resistance. This study involves the introduction of α‐hydroxy‐γ‐aminobutyric acid and amidine to the 1 and 6′ positions of sisomicin, respectively, to produce a range of 6′‐amidine modified sisomicin derivatives of AGAs. The research evaluates the antibacterial activity, absorption, distribution, metabolism, and excretion (ADME) properties, pharmacokinetic properties, cytotoxicity, nephrotoxicity, and drug resistance of AGAs. The outcomes of this study are significant in terms of enriching the structural understanding of aminoglycosides, providing insight into their structure–activity relationship, and producing new AGAs with high antibacterial activity, low ototoxicity, and nephrotoxicity. [ABSTRACT FROM AUTHOR]

The occurrence of multidrug-resistant Acinetobacter baumannii (MDRA) has increased rapidly and is associated with severe nosocomial infections. MDRA has emerged in the hospital setting and has evolved into extensively drug-resistant A. baumannii (XDRA). A clinical XDRA isolate obtained from a hospitalised patient in 2016 was evaluated for antibiotic susceptibility and whole-genome sequence. The XDRA isolate was resistant to β-lactams, including broad-spectrum cephalosporins and carbapenems, and to aminoglycosides, fosfomycin, fluoroquinolones, tetracyclines, tigecycline, and trimethoprim-sulfamethoxazole. The isolate harboured abaF , ant(3″)-II-c , aph(3″)-Ib , aph(6)-Id , armA , bla ADC-73 , bla TEM-1 , bla OXA-66 , bla OXA-23 , mphE , msrE and tet(B). Quinolone resistance was associated with mutations gyrA S81L and parC S84L. Tigecycline resistance was associated with a mutation in adeS. The isolate belonged to Oxford and Pasteur scheme sequence type 1050 and 2, respectively, and harboured a conjugative plasmid containing the aminoglycoside resistance transposon Tn aphA6. Our study demonstrates that the isolate is closely related to a recent MDRA identified in Australia and the USA, in which a similar conjugative plasmid is not observed. Although the MDRA in Australia caused an outbreak, our hospital's surveillance protocol managed to prevent a further outbreak. Our finding suggests that this XDRA isolate is of concern in hospital and community care settings. The gpi allele could be a marker for discriminating this isolate from clonal complex 92 isolates. [ABSTRACT FROM AUTHOR]

Background: Sensorineural hearing loss (SNHL) poses a major threat to both physical and mental health; however, there is still a lack of effective drugs to treat the disease. Recently, novel biological therapies, such as mesenchymal stem cells (MSCs) and their products, namely, exosomes, are showing promising therapeutic potential due to their low immunogenicity, few ethical concerns, and easy accessibility. Nevertheless, the precise mechanisms underlying the therapeutic effects of MSC-derived exosomes remain unclear. Results: Exosomes derived from MSCs reduced hearing and hair cell loss caused by neomycin-induced damage in models in vivo and in vitro. In addition, MSC-derived exosomes modulated autophagy in hair cells to exert a protective effect. Mechanistically, exogenously administered exosomes were internalized by hair cells and subsequently upregulated endocytic gene expression and endosome formation, ultimately leading to autophagy activation. This increased autophagic activity promoted cell survival, decreased the mitochondrial oxidative stress level and the apoptosis rate in hair cells, and ameliorated neomycin-induced ototoxicity. Conclusions: In summary, our findings reveal the otoprotective capacity of exogenous exosome-mediated autophagy activation in hair cells in an endocytosis-dependent manner, suggesting possibilities for deafness treatment. [ABSTRACT FROM AUTHOR]

This research focuses on combating the increasing problem of antimicrobial resistance, especially in Escherichia coli (E. coli), by assessing the efficacy of aminoglycosides. The study specifically addresses the challenge of developing new therapeutic approaches by integrating experimental data with mathematical modeling to better understand the action of aminoglycosides. It involves testing various antibiotics like streptomycin (SMN), kanamycin (KMN), gentamicin (GMN), tobramycin (TMN), and amikacin (AKN) against the O157:H7 strain of E. coli. The study employs a pharmacodynamics (PD) model to analyze how different antibiotic concentrations affect bacterial growth, utilizing minimum inhibitory concentration (MIC) to gauge the effective bactericidal levels of the antibiotics. The study's approach involved transforming bacterial growth rates, as obtained from time–kill curve data, into logarithmic values. A model was then developed to correlate these log-transformed values with their respective responses. To generate additional data points, each value was systematically increased by an increment of 0.1. To simulate real-world variability and randomness in the data, a Gaussian scatter model, characterized by parameters like κ and EC50, was employed. The mathematical modeling was pivotal in uncovering the bactericidal properties of these antibiotics, indicating different PD MIC (zMIC) values for each (SMN: 1.22; KMN: 0.89; GMN: 0.21; TMN: 0.32; AKN: 0.13), which aligned with MIC values obtained through microdilution methods. This innovative blend of experimental and mathematical approaches in the study marks a significant advancement in formulating strategies to combat the growing threat of antimicrobial-resistant E. coli, offering a novel pathway to understand and tackle antimicrobial resistance more effectively. [ABSTRACT FROM AUTHOR]

Each year over half a million people experience permanent hearing loss caused by treatment with therapeutic drugs with ototoxic side effects. There is a major unmet clinical need for therapies that protect against this hearing loss without reducing the therapeutic efficacy of these lifesaving drugs. At least 17 clinical trials evaluating 10 therapeutics are currently underway for therapies aimed at preventing aminoglycoside- and/or cisplatin-induced ototoxicity. This review describes the preclinical and clinical development of each of these approaches, provides updates on the status of ongoing trials, and highlights the importance of appropriate outcome measures in trial design and the value of reporting criteria in the dissemination of results. [ABSTRACT FROM AUTHOR]

Staphylococcus haemolyticus 010503B is a multidrug-resistant bacterium isolated from an outpatient clinic in a hospital waiting area in Thailand. Here we present the draft genome sequence of S. haemolyticus 010503B. The paired-end reads were generated on the Illumina NextSeq 550 sequencer using genomic DNA from the pure culture of S. haemolyticus 010503B. The draft genome consisted of 114 contigs with a total size of 2,457,654 base pairs, an N50 of 57,312 base pairs and a GC content of 32.60%. The dDDH between 010503B and Staphylococcus haemolyticus SM 131T was 91.9%, identifying the strain as Staphylococcus haemolyticus. The data presented holds promise for bacterial classification, comparative genomics, analysing antimicrobial resistance comprehensively, and assessing bacterial virulence factors of S. haemolyticus. The draft genome sequence data has been deposited at NCBI under Bioproject accession number PRJNA550309.

Introduction: Aminoglycoside antibiotics such as gentamicin are bactericidal and effective against gram negative organisms and act synergistically against gram positive organisms, including S taphylococcus aureus. However, they have serious adverse effects such as nephrotoxicity and ototoxicity. Gentamicin ototoxicity may occur after a single dose and results in decreased vestibular function, which is frequently debilitating and often permanent. Objective: To emphasize the risk of gentamicin ototoxicity and suggest alternative antibiotics in penicillin-allergic patients undergoing surgery. Case Summary: We present a case of a woman with preexisting Meniere's Disease who received gentamicin 400 mg perioperatively for a sigmoidectomy due to a penicillin allergy listed in the patient's medical record. The patient developed severe ototoxicity preventing her from working or driving. Physical examination was remarkable for a broad-based gait requiring assistance to walk and bilateral corrective saccades. Vestibular testing revealed high-grade bilateral vestibular loss associated with all semicircular canals, a considerable decline compared to her function 3 years prior. Discussion: Gentamicin is indicated for surgical prophylaxis when a patient has a true allergy to penicillins and cannot receive cephalosporins, though alternatives exist. True allergies include IgE-mediated illness (anaphylaxis, bronchospasm, or urticaria 30-60 minutes after administration) or exfoliative reactions (Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis). The authors encourage more prudent use of gentamicin, especially in patients susceptible for debilitating otologic insults, and offer recommendations for alternative agents prior to using gentamicin. [ABSTRACT FROM AUTHOR]

Background Evidence supporting combination treatment with a beta-lactam plus an aminoglycoside (C-BA) for endocarditis caused by viridans and gallolyticus group streptococci (VGS-GGS) with intermediate susceptibility to penicillin (PENI-I) is lacking. We assessed the clinical characteristics and outcomes of PEN-I VGS-GGS endocarditis and compared the effectiveness and safety of C-BA with third-generation cephalosporin monotherapy. Methods Retrospective analysis of prospectively collected data of a cohort of definite endocarditis caused by penicillin-susceptible and PENI-I VGS-GGS (penicillin minimum inhibitory concentration ranging from 0.25 to 2 mg/L) between 2008 and 2018 in 40 Spanish hospitals. We compared cases treated with monotherapy or with C-BA and performed multivariable analyses of risk factors for in-hospital and 1-year mortality. Results A total of 914 consecutive cases of definite endocarditis caused by VGS-GGS with complete or intermediate susceptibility to penicillin were included. A total of 688 (75.3%) were susceptible to penicillin and 226 (24.7%) were PENI-I. Monotherapy was used in 415 (45.4%) cases (cephalosporin in 331 cases) and 499 (54.6%) cases received C-BA. In-hospital mortality was 11.9%, and 190 (20.9%) patients developed acute kidney injury. Heart failure (odds ratio [OR]: 6.06; 95% confidence interval [CI]: 1.37–26.87; P =.018), central nervous system emboli (OR: 9.83; 95% CI: 2.17–44.49; P =.003) and intracardiac abscess (OR: 13.47; 95% CI: 2.24–81.08; P =.004) were independently associated with in-hospital mortality among PEN-I VGS-GGS cases, while monotherapy was not (OR: 1.01; 95% CI:.26–3.96; P =.982). Conclusions Our findings support the use of cephalosporin monotherapy in PEN-I VGS-GGS endocarditis in order to avoid nephrotoxicity without adversely affecting patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Pulmonary infections by gram-negative organisms are important in cystic fibrosis (CF). Aminoglycosides (AG) are often part of the treatment regimen. However, they are a well-known cause of ototoxicity. Even minimal hearing impairment in children could have a future impact on functional well-being.We aimed to investigate the progression of sensorineural hearing loss (SNHL) over several years in pediatric CF patients, and to identify risk factors, such as the use of AG, including both intravenous (IV) and inhaled AG. Methods: Retrospective analyses of patient records from children and adolescents followed up at the CF clinic of the Antwerp University Hospital, Belgium, were performed. We collected data on age, sex, pure-tone audiometry, and the use of AG. Descriptive and binary logistic regression analyses, and if indicated generalized estimating equations (GEE) analyses were performed. Results: Forty pediatric patients were enrolled in the study taking part from 2013 to 2020. Pure-tone audiometry revealed an important rate of SNHL over several years, with a prevalence of 29 % for high-frequency SNHL (i.e. 8 kHz). Increasing age was identified as a significant risk factor for the development of SNHL at 8 kHz if 5 or more IV AG courses (p = 0.01) were reported or when IV AG were combined with inhaled AG (p = 0.002). Conclusions: Age combined with the use of IV AG (≥5 courses or in combination with inhaled AG) are predictive for developing high-frequency SNHL (i.e. 8 kHz). We suggest routine annual hearing screening (incl. high-frequency thresholds) in CF patients, starting from childhood.

Amikacin and kanamycin are second-line injectables used in the treatment of multidrug-resistant tuberculosis (MDR-TB) based on the clinical utility of streptomycin, another aminoglycoside and first-line anti-TB drug. While streptomycin was tested as a single agent in the first controlled TB clinical trial, introduction of amikacin and kanamycin into MDR-TB regimens was not preceded by randomized controlled trials. A recent large retrospective meta-analysis revealed that compared with regimens without any injectable drug, amikacin provided modest benefits, and kanamycin was associated with worse outcomes. Although their long-term use can cause irreversible ototoxicity, they remain part of MDR-TB regimens because they have a role in preventing emergence of resistance to other drugs. To quantify the contribution of amikacin and kanamycin to second-line regimens, we applied two-dimensional matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging in large lung lesions, quantified drug exposure in lung and in lesions of rabbits with active TB, and measured the concentrations required to kill or inhibit growth of the resident bacterial populations. Using these metrics, we applied site-of-action pharmacokinetic and pharmacodynamic (PK-PD) concepts and simulated drug coverage in patients' lung lesions. The results provide a pharmacological explanation for the limited clinical utility of both agents and reveal better PK-PD lesion coverage for amikacin than kanamycin, consistent with retrospective data of contribution to treatment success. Together with recent mechanistic studies dissecting antibacterial activity from aminoglycoside ototoxicity, the limited but rapid penetration of streptomycin, amikacin, and kanamycin to the sites of TB disease supports the development of analogs with improved efficacy and tolerability.

Antimicrobial resistance is a critical public health issue that requires a thorough understanding of the factors that influence the selection and spread of antibiotic-resistant bacteria. Biocides, which are widely used in cleaning and disinfection procedures in a variety of settings, may contribute to this resistance by inducing similar defense mechanisms in bacteria against both biocides and antibiotics. However, the strategies used by bacteria to adapt and develop cross-resistance remain poorly understood, particularly within biofilms –a widespread bacterial habitat that significantly influences bacterial tolerance and adaptive strategies. Using a combination of adaptive laboratory evolution experiments, genomic and RT-qPCR analyses, and biofilm structural characterization using confocal microscopy, we investigated in this study how Escherichia coli biofilms adapted after 28 days of exposure to three biocidal active substances and the effects on cross-resistance to antibiotics. Interestingly, polyhexamethylene biguanide (PHMB) exposure led to an increase of gentamicin resistance (GenR) phenotypes in biofilms formed by most of the seven E. coli strains tested. Nevertheless, most variants that emerged under biocidal conditions did not retain the GenR phenotype after removal of antimicrobial stress, suggesting a transient adaptation (adaptive resistance). The whole genome sequencing of variants with stable GenR phenotypes revealed recurrent mutations in genes associated with cellular respiration, including cytochrome oxidase (cydA, cyoC) and ATP synthase (atpG). RT-qPCR analysis revealed an induction of gene expression associated with biofilm matrix production (especially curli synthesis), stress responses, active and passive transport and cell respiration during PHMB exposure, providing insight into potential physiological responses associated with adaptive crossresistance. In addition, confocal laser scanning microscopy (CLSM) observations demonstrated a global effect of PHMB on biofilm architectures and compositions formed by most E. coli strains, with the appearance of dense cellular clusters after a 24h-exposure. In conclusion, our results showed that the PHMB exposure stimulated the emergence of an adaptive cross-resistance to gentamicin in biofilms, likely induced through the activation of physiological responses and biofilm structural modulations altering gradients and microenvironmental conditions in the biological edifice.

Klebsiella pneumoniae are bacteria associated with respiratory tract infections and are increasingly becoming resistant to antibiotics, including carbapenems. Apramycin is a veterinary antibiotic that may have the potential to be re-purposed for use in human health, for example, for the treatment of respiratory tract infections after coupling to inhalable nanoparticles. In the present study, the antibiotic apramycin was formulated with single chain polymeric nanoparticles and tested in free and formulated forms against a set of 13 Klebsiella pneumoniae isolates (from the Netherlands and Pakistan) expressing different aminoglycoside resistance phenotypes. Minimum Inhibitory Concentration, Time Kill Kinetics and biofilm experiments were performed providing evidence for the potential efficacy of apramycin and apramycin-based nanomedicines for the treatment of human Klebsiella pneumonia infections.

In this study, we assess the scattering of light and auto-fluorescence from single bacterial cells to address the challenge of fast (<2  h), label-free phenotypic antimicrobial susceptibility testing (AST). Label-free flow cytometry is used for monitoring both the respiration-related auto-fluorescence in two different fluorescence channels corresponding to FAD and NADH, and the morphological and structural information contained in the light scattered by individual bacteria during incubation with or without antibiotic. Large multi-parameter data are analyzed using dimensionality reduction methods, based either on a combination of 2D binning and Principal Component Analysis, or with a one-class Support Vector Machine approach, with the objective to predict the Susceptible or Resistant phenotype of the strain. For the first time, both Escherichia coli (Gramnegative) and Staphylococcus epidermidis (Gram-positive) isolates were tested with a label-free approach, and, in the presence of two groups of bactericidal antibiotic molecules, aminoglycosides and beta-lactams. Our results support the feasibility of label-free AST in less than 2  h and suggest that single cell autofluorescence adds value to the Susceptible/Resistant phenotyping over singlecell scattering alone, in particular for the mecA+ Staphylococcus (i.e., resistant) strains treated with oxacillin. [ABSTRACT FROM AUTHOR]

Aminoglycoside, a medicinal category of antibiotics, are used in treatment of Gram-negative bacterial infections. Although they are the most widely-used antibiotics due to their high efficacy and low cost, several main adverse effects have been reported including nephrotoxicity and ototoxicity. Since drug-induced ototoxicity is one of the major etiological causes of acquired hearing loss, we examined cochlear hair cell damages caused by three aminoglycosides (amikacin, kanamycin, and gentamicin), and investigated protective property of an isoquinoline-type alkaloid, Berberine chloride (BC). Berberine, a well-known bioactive compound found from medicinal plants, has been known to have anti-inflammatory, antimicrobial effects. To determine protective effect of BC in aminoglycoside-induced ototoxicity, hair cell damages in aminoglycoside- and/or BC-treated hair cells using ex vivo organotypic culture system of mouse cochlea. Mitochondrial ROS levels and depolarization of mitochondrial membrane potential were analyzed, and TUNEL assay and immunostaining of cleaved caspase-3 were performed to detect apoptosis signals. As the results, it was found that BC significantly prevented aminoglycoside-induced hair cell loss and stereocilia degeneration by inhibiting excessive accumulation of mitochondrial ROS and subsequent loss of mitochondrial membrane potential. It eventually inhibited DNA fragmentation and caspase-3 activation, which were significant for all three aminoglycosides. This study is the first report suggested the preventative effect of BC against aminoglycoside-induced ototoxicity. Our data also suggests a possibility that BC has the potential to exert a protective effect against ototoxicity caused by various ototoxic drugs leading to cellular oxidative stress, not limited to aminoglycoside antibiotics. [Display omitted] • Aminoglycoside results in ototoxicity due to the overproduction of reactive oxygen species. • Berberine chloride prevents aminoglycoside-provoked increase in ROS production in cochlear explants. • Berberine chloride reduced apoptotic cell death of hair cells in cisplatin-treated cochlear explants. [ABSTRACT FROM AUTHOR]

• Nanotechnology against multidrug-resistant Acinetobacter baumannii. • Development of a nanodrug for the treatment of multidrug-resistant strains. • Antimicrobial based on AgNPs and aminoglycosides against multidrug-resistant. Multidrug-resistant bacteria are one of the world's biggest health problems; therefore, improving the spectrum of action of antibiotics could be necessary to reverse this situation. Amikacin and silver salts have well-known antimicrobial properties. However, both drugs lost their effectiveness against some bacteria, such as Acinetobacter baumannii. This work aims to develop a nanodrug from silver nanoparticles (AgNPs) functionalized with Amikacin against multidrug-resistant Acinetobacter baumannii. AgNPs were produced using the bottom-up methodology and functionalized with Amikacin modified by the carbodiimide-based chemistry, forming AgNPs@Amikacin. Susceptibility tests were performed using Amikacin-resistant Acinetobacter baumannii strains to assess the bacteriostatic and bactericidal potential of the developed nanodrug. The clinical strains were induced to form a biofilm, and biomass quantification and the metabolic activity were determined. The AgNPs have a hydrodynamic diameter of the particles with a bimodal distribution, with a size of 37.84 nm. The FT-IR spectrum of AgNPs@Amikacin exhibits vibrational modes corresponding to Amikacin, confirming the conjugation to AgNPs. Susceptibility testing demonstrated a minimal inhibitory and bactericidal concentration of < 0.5 µg/mL. The AgNPs@Amikacin reduced the biofilm metabolic activity of Acinetobacter baumannii at rates ≥ 50%, characterized by the minimal biofilm inhibition concentrations. Results demonstrate a promising development of a new nanodrug with lower concentrations, less toxicity, and greater efficacy against multidrug-resistant Acinetobacter baumannii. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this work was to integrate the Therapeutic Drug Monitoring (TDM) with the model-informed precision dosing (MIPD) approach, using Physiologically-based Pharmacokinetic/Pharmacodynamic (PBPK/PD) modelling and simulation, to explore the relationship between amikacin exposure and estimated glomerular filtration rate (GFR) in critically ill patients with cancer. Methods: In the TDM study, samples from 51 critically-ill patients with cancer treated with amikacin were analysed. Patients were stratified according to renal function based on GFR status. A full-body PBPK model with 12 organs model was developed using Simcyp V. 21, including steady-state volume of distribution of 0.21 L/kg and renal clearance of 6.9 L/h in healthy adults. PK parameters evaluated were within the 2-fold error range. Results: During the validation step, predicted vs observed amikacin clearance values after single infusion dose in patients with normal renal function, mild and moderate renal impairment were 7.6 vs 8.1 L/h (7.5 mg/kg dose); 3.8 vs 4.5 L/h (1500 mg dose) and 2.2 vs 3.1 L/h (25 mg/kg dose), respectively. However, predicted vs observed amikacin clearance after a single dose infusion of 1400 mg in critically-ill patients with cancer were 1.46 vs 1.63 (P = 0.6406) L/h (severe), 2.83 vs 1.08 (P < 0.05) L/h (moderate), 4.23 vs 2.49 (P = 0.0625) L/h (mild) and 7.41 vs 3.36 (P < 0.05) L/h (normal renal function). Conclusion: This study demonstrated that estimated GFR did not predict amikacin elimination in critically-ill patients with cancer. Further studies are necessary to find amikacin PK covariates to optimize the pharmacotherapy in this population. Therefore, TDM of amikacin is imperative in cancer patients. [ABSTRACT FROM AUTHOR]

Background: Allergic contact dermatitis (ACD) from topical ophthalmic medications (TOMs) poses an additional disease burden to patients who already suffer from eye problems. Objectives: To investigate the epidemiological/clinical profile of patients with periorbital ACD from TOMs in Turkey. Patients and Methods: This was a retrospective, cross‐sectional, single tertiary centre study based on files of 75 patch tested patients with suspected periorbital ACD from TOMs among a total of 2801 consecutively patch tested patients with suspected ACD of any origin between 1996 and 2019. Results: Periorbital ACD was diagnosed in 25 of 75 (33.3%) patients (female:male = 1.8:1; age range: 6–85 years) with suspected ACD from TOMs showing an overall prevalence of 0.9% (25/2801) among the whole patch test population. Atopy was not present. Tobramycin‐containing TOMs were the most frequent culprits, followed by antiglaucoma preparations. Their frequency increased, whereas no new cases of neomycin‐induced ACD were observed after 2011. Positivities with thimerosal were of unknown clinical relevance, while benzalkonium chloride (BAC) caused ACD in two patients. The diagnosis would be missed in each 20% of patients without performing day (D) 4 and D7 readings and strip‐patch testing. Ten culprits were identified only by testing with patients' own TOMs in eight (32%) patients. Conclusions: Aminoglycosides, particularly tobramycin, were the leading cause of ACD from TOMs. The frequency of ACD from tobramycin and antiglaucoma medications increased after 2011. BAC was a rare but important allergen. Additional D4 and D7 readings, strip‐patch testing, and testing with patients' own TOMs seem essential when patch testing with eye medications. [ABSTRACT FROM AUTHOR]

Aminoglycosides are among the antibiotics frequently used worldwide due to their low cost, high efficacy, and relatively low bacterial resistance compared to other antibiotics. Despite their widespread use and positive effects, the possibility of accumulating in the renal proximal tubule epithelial cells and causing toxicity limits the comfortable use of these drugs. Although many pharmacological agents have been tried in experimental animals in the hope of being protective against nephrotoxicity that may occur due to aminoglycosides, no nephroprotectant agent that is used routinely has been found yet. Gentamicin has been used as a prototype of aminoglycosides to induce nephrotoxicity in most studies. Antioxidant indices, inflammatory responses, and apoptotic markers were evaluated to assess possible protective efficacy. Natural products, vitamins and minerals, hormones, and many conventional drugs have shown potential effects to prevent nephrotoxicity. In addition, it is seen that the results may vary not only according to the agent used but also the method and duration of administration. Although there are many studies on the subject, it is clear that more research is needed to obtain clear results. In this study, preclinical studies conducted in rodents over the last ten years using gentamicin, an aminoglycoside with the potential to cause nephrotoxicity, were reviewed. In studies on this subject, agents used for treatment and protection were grouped as natural products, minerals and vitamins, hormones, chemical agents and conventional drugs, and it was tried to show how wide a spectrum the agents used were. By providing information about the parameters used in the evaluation in each study, it is aimed to contribute to standardization so that studies can be compared in future studies. [ABSTRACT FROM AUTHOR]

Introduction: Parenteral administration of gentamicin is a globally known therapeutic strategy for severe infections, including severe community acquired pneumonia, complex severe acute malnourishment, neonatal and pediatric sepsis. The drug is also prescribed as an ophthalmologic anti-infective. In most cases, the therapeutic course necessitates frequent bolus medication doses, lengthy hospitalization, and ongoing therapeutic monitoring; hence a qualified healthcare provider is required. Objectives: Gentamicin is a hydrophilic drug and has a short half-life, making it difficult to achieve appropriate systemic concentrations when taken parenterally. The use of innovative oral medication delivery systems is justified in this context. Furthermore, new delivery strategies can increase the membrane permeability of gentamicin. Conclusion: The current analysis provides a detailed summary of gentamicin's research history as well as several developing drug delivery strategies that have been explored. The examples included in the paper give important evidence on innovative delivery systems for gentamicin in the domain of antimicrobial investigations opening a way for upcoming therapeutics that may provide better clinical outcomes. [ABSTRACT FROM AUTHOR]

Choosing the appropriate antibiotics to treat bacterial infections has grown more challenging as a result of the emergence of antibiotic-resistant bacteria. Aminoglycosides, as broad-spectrum antibiotics, are increasingly being used clinically; however, for most effective employment of aminoglycosides, a comprehensive understanding of aminoglycoside resistance genes’ prevalence and dissemination is required. Therefore, to better understand the global resistance status of aminoglycoside antibiotics and the prevalence of antibiotic-resistance genes (ARGs) in various bacterial species, this systematic review gathered relevant data from multiple studies. Two primary resistance mechanisms—aminoglycoside enzymatic modification and 16S rRNA methylation—were assessed, and the prevalence of the corresponding ARGs was described. The coexistence of aminoglycoside ARGs with other ARGs was also demonstrated, as was the relationship between aminoglycoside ARGs and resistant phenotypes. The lack of effective therapeutic agents to combat resistant pathogens presents a real threat to public health. The combination of aminoglycosides with other antibiotics may provide a novel treatment strategy.

Abstract Background The assumptions of conventional spatial models cannot estimate the responses across space and over time. Here we propose new spatial panel data models to investigate the association between the risk factors and incidence of end-stage renal disease (ESRD). Methods A longitudinal (panel data) study was conducted using data from the National Health Insurance Database in Taiwan. We developed an algorithm to identify the patient’s residence and estimate the ESRD rate in each township. Corresponding covariates, including patient comorbidities, history of medication use, and socio-environmental factors, were collected. Local Indicators of Spatial Association were used to describe local spatial clustering around an individual location. Moreover, a spatial panel data model was proposed to investigate the association between ESRD incidence and risk factors. Results In total, 73,995 patients with ESRD were included in this study. The western region had a higher proportion of high incidence rates than the eastern region. The proportion of high incidence rates in the eastern areas increased over the years. We found that most “social environmental factors,” except average income and air pollution (PM 2.5 and PM10), had a significant influence on the incidence rate of ESRD when considering spatial dependences of response and explanatory variables. Receiving non-steroidal anti-inflammatory drugs and aminoglycosides within 90 days prior to ESRD had a significant positive effect on the ESRD incidence rate. Conclusion Future comprehensive studies on townships located in higher-risk clusters of ESRD will help in designing healthcare policies for suitable action.

G-quadruplex-forming nucleic acids have evolved to have applications in biology, drug design, sensing, and nanotechnology, to name a few. Together with the structural understanding, several attempts have been made to discover and design new classes of chemical agents that target these structures in the hope of using them as future therapeutics. Here, we report the binding of aminoglycosides, in particular neomycin, to parallel G-quadruplexes that exist as G-quadruplex monomers, dimers, or compounds that have the propensity to form dimeric G-quadruplex structures. Using a combination of calorimetric and spectroscopic studies, we show that neomycin binds to the parallel G-quadruplex with affinities in the range of Ka ∼ 105–108 M-1, which depends on the base composition, ability to form dimeric G-quadruplex structures, salt, and pH of the buffer used. At pH 7.0, the binding of neomycin was found to be electrostatically driven potentially through the formation of ion pairs formed with the quadruplex. Lowering the pH resulted in neomycin’s association constants in the range of Ka ∼ 106–107 M-1 in a salt dependent manner. Circular dichroism (CD) studies showed that neomycin’s binding does not cause a change in the parallel conformation of the G-quadruplex, yet some binding-induced changes in the intensity of the CD signals were seen. A comparative binding study of neomycin and paromomycin using d(UG4T) showed paromomycin binding to be much weaker than neomycin, highlighting the importance of ring I in the recognition process. In toto, our results expanded the binding landscape of aminoglycosides where parallel G-quadruplexes have been discovered as one of the high-affinity sites. These results may offer a new understanding of some of the undesirable functions of aminoglycosides and help in the design of aminoglycoside-based G-quadruplex binders of high affinity.

tRNA methyltransferase 9 (Trm9)‐catalysed tRNA modifications have been shown to translationally enhance the DNA damage response (DDR). Here, we show that Saccharomyces cerevisiae trm9Δ, distinct DNA repair and spindle assembly checkpoint (SAC) mutants are differentially sensitive to the aminoglycosides tobramycin, gentamicin and amikacin, indicating DDR and SAC activation might rely on translation fidelity, under aminoglycoside stress. Further, we report that the DNA damage induced by aminoglycosides in the base excision repair mutants ogg1Δ and apn1Δ is mediated by reactive oxygen species, which induce the DNA adduct 8‐hydroxy deoxyguanosine. Finally, the synergistic effect of tobramycin and the DNA‐damaging agent bleomycin to sensitize trm9Δ and the DDR mutants mlh1Δ, rad51Δ, mre11Δ and sgs1Δ at significantly lower concentrations compared with wild‐type suggests that cells with tRNA modification dysregulation and DNA repair gene defects can be selectively sensitized using a combination of translation inhibitors and DNA‐damaging agents. [ABSTRACT FROM AUTHOR]

Using cryo-electron microscopy (cryo-EM), we determined the structure of the Escherichia coli 70S ribosome with a global resolution of 2.0 Å. The maps reveal unambiguous positioning of protein and RNA residues, their detailed chemical interactions, and chemical modifications. Notable features include the first examples of isopeptide and thioamide backbone substitutions in ribosomal proteins, the former likely conserved in all domains of life. The maps also reveal extensive solvation of the small (30S) ribosomal subunit, and interactions with A-site and P-site tRNAs, mRNA, and the antibiotic paromomycin. The maps and models of the bacterial ribosome presented here now allow a deeper phylogenetic analysis of ribosomal components including structural conservation to the level of solvation. The high quality of the maps should enable future structural analyses of the chemical basis for translation and aid the development of robust tools for cryo-EM structure modeling and refinement.

Abstract Background The treatment of swine dysentery (SD) has become constrained in recent years due to the limited availability of effective drugs combined with a rise in antimicrobial resistance. Gentamicin, an aminoglycoside antibiotic, is authorised for the control of this disease in several European countries but has not been extensively used so far. In this study, the in vitro susceptibility of 56 Brachyspira hyodysenteriae field isolates was evaluated against gentamicin using a broth microdilution test. The molecular basis of decreased susceptibility to gentamicin was also investigated by sequencing the 16S rRNA gene and phylogenetic relatedness by multiple-locus variable number tandem-repeat analysis (MLVA). Results Most B. hyodysenteriae isolates presented low minimum inhibitory concentration (MIC) values to gentamicin, with a mode of 2 µg/mL, a median or MIC50 of 4 µg/mL and percentile 90 or MIC90 of 16 µg/mL. The distribution of these values over the period studied (2011–2019) did not show a tendency towards the development of resistance to gentamicin. Differences in susceptibility among isolates could be explained by two point-mutations in the 16S rRNA gene, C990T and A1185G, which were only present in isolates with high MICs. These isolates were typed in three different MLVA clusters. Analyses of co-resistance between gentamicin and antimicrobials commonly used for the treatment of SD revealed that resistance to tiamulin and valnemulin was associated with low MICs for gentamicin. Conclusions The results provide an accurate characterisation of antimicrobial sensitivity to gentamicin and possible mechanisms of resistance in Spanish B. hyodysenteriae isolates. These findings allow us to propose gentamicin as an alternative in the antibiotic management of SD, particularly in outbreaks caused by pleuromutilin resistant isolates.

Background: Gentamicin (GNT) is a highly effective aminoglycoside antibiotic that is commonly used to treat life-threatening bacterial infections. Aim: The aim of the current study is to determine whether tadalafil can protect against GNT-induced nephrotoxicity. Methods: Twenty-four male Albino rats were used in the study, which were randomly divided into four groups, six animals each. Control untreated group received distilled water (5ml/kg, P.O) for 12 days and on days 6-12, they received (5ml/kg,i.p) normal saline daily, one hour after oral administration of distilled water. Tadalafil group received tadalafil (5mg/kg, P.O) for 12 days and on days 6-12, they received (5ml/kg,i.p) of normal saline daily, one hour after oral administration of tadalafil. Gentamicin group received distilled water (5ml/kg, P.O) and on days 6-12, they received gentamicin (100mg/kg,i.p) one hour after oral administration of distilled water. Gentamicin+Tadalafil group received tadalafil (5mg/kg, P.O) for 12 days and on days 6-12, they received gentamicin (100mg/kg,i.p) one hour after oral administration of tadalafil. Body weight and kidney weight were investigated. Urine volume as well as urinary albumin, creatinine, creatinine clearance and albumin /creatinine ratio (ACR) were evaluated. Besides, serum levels of urea and creatinine were measured as kidney function parameters. Renal tissues oxidative stress markers as malondialdehyde (MDA) and the antioxidant enzymes as superoxide dismutase (SOD) and catalase (CAT) activities. Renal cortex nitric oxide (NO) and kidney injury molecule-1 (KIM-1) were evaluated. Histological analysis and immunohistochemical expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) were performed. The results of the present study showed that GNT decreased creatinine clearance and increased the serum levels of renal function parameters. GNT caused a significant increase in renal cortex MDA, NO and urine levels of KIM-1, while it decreased CAT and SOD activities. Gentamicin administration resulted in increased immunohistochemical expression of iNOS enzyme while decreasing eNOS expression. Renal corpuscles and tubules also showed histological and ultrastructural changes. Pretreatment with tadalafil, on the other hand, reversed the effects of GNT administration. In conclusion, findings of the present study indicate that tadalafil reduces GNT-induced kidney damage by inhibition of inflammation, oxidative stress, and apoptosis.

Bacterial keratitis is the most common corneal infection which may lead to blindness, and seriously threatened the human visual health worldwide. Clinical treatment with antibiotic eye drops formulation usually falls in low bioavailability and poor therapeutic efficiency. Hydrogel has gained much attention as ophthalmic formulation recently due to the prolonged drug retention on ocular surface. In this study, we proposed a type of all-small-molecule supramolecular hydrogel assembled from guanosine-5′-monophosphate disodium salt and tobramycin for the treatment of bacterial keratitis. Guanosine-5′-monophosphate disodium salt assembled into guanosine-quartet nanofibers via hydrogen bonding and π-π stacking, and tobramycin with five primary amine groups further crosslinked the nanofibers bearing multiple phosphate moieties into gel networks via ionic interactions. The supramolecular gel showed shear thinning and thixotropic properties, good biocompatibility, and antibacterial activity. The gel treatment significantly ameliorated P. aeruginosa induced bacterial keratitis, and showed higher therapeutic efficacy compared to tobramycin eye drop. This study provides a facile and efficient antibiotic gel formulation for clinical treatment of bacterial keratitis.

Approximately 11% of genetic human diseases are caused by nonsense mutations that introduce a premature termination codon (PTC) into the coding sequence. The PTC results in the production of a potentially harmful shortened polypeptide and activation of a nonsense-mediated decay (NMD) pathway. The NMD pathway reduces the burden of unproductive protein synthesis by lowering the level of PTC mRNA. There is an endogenous rescue mechanism that produces a full-length protein from a PTC mRNA. Nonsense suppression therapies aim to increase readthrough, suppress NMD, or are a combination of both strategies. Therefore, treatment with translational readthrough-inducing drugs (TRIDs) and NMD inhibitors may increase the effectiveness of PTC suppression. Here we discuss the mechanism of PTC readthrough and the development of novel approaches to PTC suppression. We also discuss the toxicity and bioavailability of therapeutics used to stimulate PTC readthrough. [ABSTRACT FROM AUTHOR]

Plazomicin is a recent U.S. Food and Drug Administration (FDA)-approved semisynthetic aminoglycoside. Its structure consists of a sisomicin scaffold modified by adding a 2(S)-hydroxy aminobutyryl group at the N1 position and a hydroxyethyl substituent at the 6′ position. These substitutions produced a molecule refractory to most aminoglycoside-modifying enzymes. The main enzyme within this group that recognizes plazomicin as substrate is the aminoglycoside 2′-N-acetyltransferase type Ia [AAC(2′)-Ia], which reduces the antibiotic's potency. Designing formulations that combine an antimicrobial with an inhibitor of resistance is a recognized strategy to extend the useful life of existing antibiotics. We have recently found that several metal ions inhibit the enzymatic inactivation of numerous aminoglycosides mediated by the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib]. In particular, Ag+, which also enhances the effect of aminoglycosides by other mechanisms, is very effective in interfering with AAC(6′)-Ib-mediated resistance to amikacin. Here we report that silver acetate is a potent inhibitor of AAC(2′)-Ia-mediated acetylation of plazomicin in vitro, and it reduces resistance levels of Escherichia coli carrying aac(2′)-Ia. The resistance reversion assays produced equivalent results when the structural gene was expressed under the control of the natural or the blaTEM-1 promoters. The antibiotic effect of plazomicin in combination with silver was bactericidal, and the mix did not show significant toxicity to human embryonic kidney 293 (HEK293) cells. [ABSTRACT FROM AUTHOR]

Background: Enterococci are main normal microbial flora of both humans and animals and can survive in a diverse range of environments. These bacteria carry out aminoglycoside and vancomycin resistance genes and spread them in environment by many routs such as chicken meat products. The present study was aimed to determine the frequency of aminoglycoside and vancomycin resistant genes in Enterococcus species isolated from chicken meat specimens. Methods: A total of 250 chicken raw meat specimens was prepared from slaughterhouses at Zanjan province, cultured at BHI broth and incubated at 37°C for 24h. The positive cultures were sub-cultured in blood agar plates and grown colonies identified using phenotypical and biochemical tests. Antibiotic susceptibility was determined according to the Clinical and Laboratory Standards Institute (CLSI) standards and PCR assays were performed to detect vanA, vanB, aph (2")1c, aph (2")1b, aph (2")1d, ant(3'), aph(3')IIIa, ant(4')1a, ant(6') and aac(6') genes. Results: In total, 100 Enterococcus species isolated from 250 specimens and 35% of them belonged to E. faecalis and the others were E. faecium (65%). The prevalence of the vanA, vanB, aph (2")1c, aph (2")1b, aph (2")1d, ant(3'), aph(3')IIIa, ant(4')1a, ant(6') and aac(6') genes among the 100 Enterococcus species was 14%, 12%, 10%, 1%, 2%, 50%, 26%, 9%, 18% and 22%, respectively. Conclusion: The current study revealed that the rate of antimicrobial resistance genes to aminoglycosides and vancomycin was worrying and health measurements in meat products industries must be performed to prevent spread of antimicrobial resistance elements among bacteria. [ABSTRACT FROM AUTHOR]

Background and Aim: Shigella is the causative agent of shigellosis in the world. Antibiotic treatment is important in this bacterium, but recently Shigella species containing the aph, aadE, aacA-aphD genes have shown resistance to aminoglycosides and have hampered the treatment process. Therefore, the aim of this study is a molecular investigation of Shigella dysenteriae aminoglycoside resistance genes isolated from children and its expression under the influence of curcumin nanoparticles. Materials and Methods: In this study, 60 diarrhea samples collected from Tehran hospitals in 2022 were used. Shigella dysenteriae isolates were identified by biochemical and microbial tests. The presence of aadE, aacA-aphD, and aph genes was confirmed by the Multiplex-PCR method. Then, real-time PCR was used to investigate the expression of aadE gene in the presence of curcumin nanoparticles. Results: From the 60 diarrhea samples examined, 12 strains (40%) of Shigella dysenteriae were identified by biochemical tests. Ten isolates (83.3%) carried the aadE gene, six isolates carried the aacA_aphD gene, and one isolate carried the aph gene. The Sub MIC value of curcumin nanoparticles on aadE gene expression is 128 µg/mL, and the Fold Change for this gene is -1.03. Conclusion: Considering the presence of aadE gene in 83.3% of S. dysenteriae isolates, it is important to investigate the presence of this gene in providing a suitable treatment model for patients infected with this bacterium, as well as the expression of aadE gene as the most common one. The expression of the aminoglycoside resistance gene was reduced to a relative amount in the presence of curcumin nanoparticles. Therefore, curcumin nanoparticles can be a suitable alternative for the treatment of strains carrying aminoglycoside resistance genes. [ABSTRACT FROM AUTHOR]

Following the discovery of streptomycin from Streptomyces griseus in the 1940s by Selman Waksman and colleagues, aminoglycosides were first used to treat tuberculosis and then numerous derivatives have since been used to combat a wide variety of bacterial infections. These bactericidal antibiotics were used as first-line treatments for several decades but were largely replaced by ß-lactams and fluoroquinolones in the 1980s, although widespread emergence of antibiotic-resistance has led to renewed interest in aminoglycosides. The primary site of action for aminoglycosides is the 30 S ribosomal subunit where they disrupt protein translation, which contributes to widespread cellular damage through a number of secondary effects including rapid uptake of aminoglycosides via elevated proton-motive force (PMF), membrane damage and breakdown, oxidative stress, and hyperpolarisation of the membrane. Several factors associated with aminoglycoside entry have been shown to impact upon bacterial killing, and more recent work has revealed a complex relationship between metabolic states and the efficacy of different aminoglycosides. Hence, it is imperative to consider the environmental conditions and bacterial physiology and how this can impact upon aminoglycoside entry and potency. This mini-review seeks to discuss recent advances in this area and how this might affect the future use of aminoglycosides. [ABSTRACT FROM AUTHOR]

This research focuses on combating the increasing problem of antimicrobial resistance, especially in Escherichia coli (E. coli), by assessing the efficacy of aminoglycosides. The study specifically addresses the challenge of developing new therapeutic approaches by integrating experimental data with mathematical modeling to better understand the action of aminoglycosides. It involves testing various antibiotics like streptomycin (SMN), kanamycin (KMN), gentamicin (GMN), tobramycin (TMN), and amikacin (AKN) against the O157:H7 strain of E. coli. The study employs a pharmacodynamics (PD) model to analyze how different antibiotic concentrations affect bacterial growth, utilizing minimum inhibitory concentration (MIC) to gauge the effective bactericidal levels of the antibiotics. The study’s approach involved transforming bacterial growth rates, as obtained from time–kill curve data, into logarithmic values. A model was then developed to correlate these log-transformed values with their respective responses. To generate additional data points, each value was systematically increased by an increment of 0.1. To simulate real-world variability and randomness in the data, a Gaussian scatter model, characterized by parameters like κ and EC50, was employed. The mathematical modeling was pivotal in uncovering the bactericidal properties of these antibiotics, indicating different PD MIC (zMIC) values for each (SMN: 1.22; KMN: 0.89; GMN: 0.21; TMN: 0.32; AKN: 0.13), which aligned with MIC values obtained through microdilution methods. This innovative blend of experimental and mathematical approaches in the study marks a significant advancement in formulating strategies to combat the growing threat of antimicrobial-resistant E. coli, offering a novel pathway to understand and tackle antimicrobial resistance more effectively.

Evidence suggests that otologic injury from ototopical aminoglycoside preparations is infrequent when used to treat ear infections with an intact tympanic membrane. Meanwhile, parenteral administration of aminoglycosides, is well known to be associated with a significant incidence of cochlear and vestibular damage. The discrepancy between topical and parenteral ototoxic effects is thought to result from a combination of factors, including the protective function of debris overlying the round window membrane, low antibiotic concentrations of topical antibiotic preparations, length of exposure and inability to detect subtle hearing or vestibular changes. Herein, we present a case of acute vestibulopathy following a 2-week course of topical gentamicin otic drops. Awareness of vestibulotoxicity following topical gentamicin therapy is prudent as vestibulopathic symptoms can be severely debilitating. [ABSTRACT FROM AUTHOR]