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Journal of the Pediatric Infectious... Feb 2020Infections due to carbapenem-resistant Enterobacteriaceae (CRE) are increasingly prevalent in children and are associated with poor clinical outcomes. Optimal treatment... (Review)
Review
Infections due to carbapenem-resistant Enterobacteriaceae (CRE) are increasingly prevalent in children and are associated with poor clinical outcomes. Optimal treatment strategies for CRE infections continue to evolve. A lack of pediatric-specific comparative effectiveness data, uncertain pediatric dosing regimens for several agents, and a relative lack of new antibiotics with pediatric indications approved by the US Food and Drug Administration (FDA) collectively present unique challenges for children. In this review, we provide a framework for antibiotic treatment of CRE infections in children, highlighting relevant microbiologic considerations and summarizing available data related to the evaluation of FDA-approved antibiotics (as of September 2019) with CRE activity, including carbapenems, ceftazidime-avibactam, meropenem-vaborbactam, imipenem/cilastatin-relebactam, polymyxins, tigecycline, eravacycline, and plazomicin.
Topics: Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Child; Drug Therapy, Combination; Enterobacteriaceae Infections; Humans; Polymyxins; Sisomicin; Tetracyclines; Tigecycline; beta-Lactamase Inhibitors
PubMed: 31872226
DOI: 10.1093/jpids/piz085 -
Molecules (Basel, Switzerland) May 2021The present work aims to examine the worrying problem of antibiotic resistance and the emergence of multidrug-resistant bacterial strains, which have now become really... (Review)
Review
The present work aims to examine the worrying problem of antibiotic resistance and the emergence of multidrug-resistant bacterial strains, which have now become really common in hospitals and risk hindering the global control of infectious diseases. After a careful examination of these phenomena and multiple mechanisms that make certain bacteria resistant to specific antibiotics that were originally effective in the treatment of infections caused by the same pathogens, possible strategies to stem antibiotic resistance are analyzed. This paper, therefore, focuses on the most promising new chemical compounds in the current pipeline active against multidrug-resistant organisms that are innovative compared to traditional antibiotics: Firstly, the main antibacterial agents in clinical development (Phase III) from 2017 to 2020 are listed (with special attention on the treatment of infections caused by the pathogens , including multidrug-resistant isolates, and ), and then the paper moves on to the new agents of pharmacological interest that have been approved during the same period. They include tetracycline derivatives (eravacycline), fourth generation fluoroquinolones (delafloxacin), new combinations between one β-lactam and one β-lactamase inhibitor (meropenem and vaborbactam), siderophore cephalosporins (cefiderocol), new aminoglycosides (plazomicin), and agents in development for treating drug-resistant TB (pretomanid). It concludes with the advantages that can result from the use of these compounds, also mentioning other approaches, still poorly developed, for combating antibiotic resistance: Nanoparticles delivery systems for antibiotics.
Topics: Animals; Anti-Bacterial Agents; Boronic Acids; Cephalosporins; Chemistry, Pharmaceutical; Clostridioides difficile; Clostridium Infections; Drug Design; Drug Resistance, Multiple, Bacterial; Fluoroquinolones; Gonorrhea; Humans; Meropenem; Neisseria gonorrhoeae; Nitroimidazoles; Sisomicin; Tetracyclines; beta-Lactamase Inhibitors; Cefiderocol
PubMed: 34063264
DOI: 10.3390/molecules26092671 -
The FEBS Journal Mar 2021Interactions between aminoglycoside antibiotics and the twister ribozyme were investigated in this study. An initial screen of 17 RNA-binding antibiotics showed that a...
Interactions between aminoglycoside antibiotics and the twister ribozyme were investigated in this study. An initial screen of 17 RNA-binding antibiotics showed that a number of aminoglycosides inhibit the ribozyme, while a subset of aminoglycosides enhances twister cleavage. Initial kinetic analysis of the twister ribozyme showed a sevenfold inhibition of ribozyme cleavage by paromomycin and a fivefold enhancement of cleavage by sisomicin. Direct binding between the twister ribozyme RNA and paromomycin or sisomicin was measured by microscale thermophoresis. Selective 2'-hydroxyl acylation analysed by primer extension shows that both paromomycin and sisomicin induce distinctive tertiary structure changes to the twister ribozyme. Published crystal structures and mechanistic analysis of the twister ribozyme have deduced a nucleobase-mediated general acid-base catalytic mechanism, in which a conserved guanine plays a key role. Here, we show that paromomycin binding induces a structural transition to the twister ribozyme such that a highly conserved guanine in the active site becomes displaced, leading to inhibition of cleavage. In contrast, sisomicin binding appears to change interactions between P3 and L2, inducing allosteric changes to the active site that enhance twister RNA cleavage. Therefore, we show that small-molecule binding can modulate twister ribozyme activity. These results suggest that aminoglycosides may be used as molecular tools to study this widely distributed ribozyme.
Topics: Animals; Anti-Bacterial Agents; Base Pairing; Base Sequence; Biocatalysis; Catalytic Domain; Kinetics; Models, Molecular; Nucleic Acid Conformation; Oligoribonucleotides; Paromomycin; RNA, Catalytic; Sisomicin; Wasps
PubMed: 32790122
DOI: 10.1111/febs.15517 -
Nature Communications Nov 2022Type 1 diabetes (T1D) is an autoimmune disease, characterized by the presence of autoantibodies to protein and non-protein antigens. Here we report the identification of...
Type 1 diabetes (T1D) is an autoimmune disease, characterized by the presence of autoantibodies to protein and non-protein antigens. Here we report the identification of specific anti-carbohydrate antibodies (ACAs) that are associated with pathogenesis and progression to T1D. We compare circulatory levels of ACAs against 202 glycans in a cross-sectional cohort of T1D patients (n = 278) and healthy controls (n = 298), as well as in a longitudinal cohort (n = 112). We identify 11 clusters of ACAs associated with glycan function class. Clusters enriched for aminoglycosides, blood group A and B antigens, glycolipids, ganglio-series, and O-linked glycans are associated with progression to T1D. ACAs against gentamicin and its related structures, G418 and sisomicin, are also associated with islet autoimmunity. ACAs improve discrimination of T1D status of individuals over a model with only clinical variables and are potential biomarkers for T1D.
Topics: Humans; Diabetes Mellitus, Type 1; Glycomics; Cross-Sectional Studies; Autoimmunity; Autoantibodies; Polysaccharides
PubMed: 36316364
DOI: 10.1038/s41467-022-34341-2 -
Research Square Apr 2024Hearing impairment arises from the loss of either type of cochlear sensory hair cells. Inner hair cells act as primary sound transducers, while outer hair cells enhance...
Hearing impairment arises from the loss of either type of cochlear sensory hair cells. Inner hair cells act as primary sound transducers, while outer hair cells enhance sound-induced vibrations within the organ of Corti. Established models, such as systemic administration of ototoxic aminoglycosides, yield inconsistent and variable hair cell death in mice. Overcoming this limitation, we developed a method involving surgical delivery of a hyperosmotic sisomicin solution into the posterior semicircular canal of adult mice. This procedure induced rapid and synchronous apoptotic demise of outer hair cells within 14 hours, leading to irreversible hearing loss. The combination of sisomicin and hyperosmotic stress caused consistent and synergistic ototoxic damage. Inner hair cells remained intact until three days post-treatment, after which deterioration in structure and number was observed, culminating in cell loss by day seven. This robust animal model provides a valuable tool for otoregenerative research, facilitating single-cell and omics-based studies toward exploring preclinical therapeutic strategies.
PubMed: 38645253
DOI: 10.21203/rs.3.rs-4096027/v1 -
Kidney International Dec 1976Aminoglycoside antibiotics seem to accumulate and persist in the kidney. For a better understanding of this problem, groups of six rats received a single 4 mg/kg i.p....
Aminoglycoside antibiotics seem to accumulate and persist in the kidney. For a better understanding of this problem, groups of six rats received a single 4 mg/kg i.p. injection of sisomicin and were sacrificed repeatedly from 30 min to 28 days later. Sisomicin concentrations (bioassay) decreased rapidly in the serum, lung and other tissues. There was only a trace at six hours. The situation was totally different for the kidney. Concentrations in the cortex increased up to six hours with a maximum of 99 mug/g, 11 times higher than the peak value in the serum then decreased very slowly to 56, 18, and 7 mug/g, 2, 14 and 28 days, respecitvely, after injection. The concentrations in the medulla were lower than in the cortex but also showed an accumulation and persistence. Similar results were observed with gentamicin. In another experiment, daily injections of sisomicin or gentamicin during seven days demonstrated that the concentrations of both antibiotics six hours after the last injection were nearly three times higher in the cortex and twice as high in the medulla than after a single injection. These data explain why the nephrotoxicity of sisomicin or gentamicin involves chiefly the cortex, increases with the length of the treatment and can persist for several weeks after the last injection. Therapeutic implications need further studies.
Topics: Animals; Anti-Bacterial Agents; Gentamicins; Half-Life; Kidney; Kidney Cortex; Kidney Medulla; Kinetics; Lung; Male; Rats; Sisomicin; Time Factors
PubMed: 1011538
DOI: 10.1038/ki.1976.131 -
International Journal of Molecular... Mar 2022Pathogenic CUG and CCUG RNA repeats have been associated with myotonic dystrophy type 1 and 2 (DM1 and DM2), respectively. Identifying small molecules that can bind...
Pathogenic CUG and CCUG RNA repeats have been associated with myotonic dystrophy type 1 and 2 (DM1 and DM2), respectively. Identifying small molecules that can bind these RNA repeats is of great significance to develop potential therapeutics to treat these neurodegenerative diseases. Some studies have shown that aminoglycosides and their derivatives could work as potential lead compounds targeting these RNA repeats. In this work, sisomicin, previously known to bind HIV-1 TAR, is investigated as a possible ligand for CUG RNA repeats. We designed a novel fluorescence-labeled RNA sequence of r(CUG) to mimic cellular RNA repeats and improve the detecting sensitivity. The interaction of sisomicin with CUG RNA repeats is characterized by the change of fluorescent signal, which is initially minimized by covalently incorporating the fluorescein into the RNA bases and later increased upon ligand binding. The results show that sisomicin can bind and stabilize the folded RNA structure. We demonstrate that this new fluorescence-based binding characterization assay is consistent with the classic UV technique, indicating its feasibility for high-throughput screening of ligand-RNA binding interactions and wide applications to measure the thermodynamic parameters in addition to binding constants and kinetics when probing such interactions.
Topics: Fluorescence; Humans; Ligands; Myotonic Dystrophy; RNA; RNA-Binding Proteins; Sisomicin
PubMed: 35328743
DOI: 10.3390/ijms23063321 -
The Journal of Antibiotics Jul 1976A sisomicin fermentation carried out in the presence of (methyl-14C)-L-methionine resulted in a crude mixture, composed of methyl-14C-labeled sisomicin as a major...
A sisomicin fermentation carried out in the presence of (methyl-14C)-L-methionine resulted in a crude mixture, composed of methyl-14C-labeled sisomicin as a major component; and two 4''-C-desmethylsisomicin (66-40B and 66-40D) isomer-like components, an unidentified component and a gentamicin A-like antibiotic as minor components. When (methyl-14C)-L-methionine was added in an early stage of the fermentation (24 hours), incorporation of methyl-14C-label into polar components (e.g., gentamicin A-like antibiotic) preceded that into sisomicin. Chromatographic evidence for the bioconversion of (methyl-14C)-gentamicin A to a radioactive sisomicin-like product (possibly (3''-N-methyl-14C)-sisomicin) was seen, when a Micromonospora blocked mutant was incubated in the presence of the former antibiotic.
Topics: Anti-Bacterial Agents; Biotransformation; Fermentation; Gentamicins; Methionine; Micromonospora; Sisomicin; Time Factors
PubMed: 956052
DOI: 10.7164/antibiotics.29.677 -
Internal and Emergency Medicine Nov 2021Antimicrobial resistance is a growing threat to public health and an increasingly common problem for acute care physicians to confront. Several novel antibiotics have... (Review)
Review
Antimicrobial resistance is a growing threat to public health and an increasingly common problem for acute care physicians to confront. Several novel antibiotics have been approved in the past decade to combat these infections; however, physicians may be unfamiliar with how to appropriately utilize them. The purpose of this review is to evaluate novel antibiotics active against resistant gram-negative bacteria and highlight clinical information regarding their use in the acute care setting. This review focuses on novel antibiotics useful in the treatment of infections caused by resistant gram-negative organisms that may be seen in the acute care setting. These novel antibiotics include ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, imipenem/cilistatin/relebactam, cefiderocol, plazomicin, eravacycline, and omadacycline. Acute care physicians should be familiar with these novel antibiotics so they can utilize them appropriately.
Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Boronic Acids; Ceftazidime; Cephalosporins; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Design; Drug Resistance, Multiple; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Heterocyclic Compounds, 1-Ring; Humans; Meropenem; Sisomicin; Tazobactam; Tetracyclines; Cefiderocol
PubMed: 33956311
DOI: 10.1007/s11739-021-02749-1