- Design and synthesis of biologically active cationic amphiphiles built on the calixarene scaffold. [Journal Article]
- IJInt J Pharm 2018 Aug 14
- A promising strategy to design safer and more effective cationic lipids for gene delivery with inherent antibacterial properties is to covalently tether a lipophilic moiety with oligomeric aminoglyco...
A promising strategy to design safer and more effective cationic lipids for gene delivery with inherent antibacterial properties is to covalently tether a lipophilic moiety with oligomeric aminoglycosides (AGs), a large family of Gram-negative-active antibiotics. Herein, we reported the development of a new class of multicationic-head AG-based amphiphiles built on the tetramino-tetrahexyloxycalixarene (4A4Hex-calix-calix) scaffold. Three different conjugates, namely 4A4Hex-calix-calix-neomycin, -neamine, and -paromomycin, were synthesized and characterized. Due to the inherent multivalency of AGs and the amphiphilic behaviour, every 4A4Hex-calix-calix-AG exhibited greater DNA binding ability than the gold standard transfectant 25 kDa bPEI and striking DNA packing ability. DNA/4A4Hex-calix-calix-AG complexes at charge ratios (CRs, +/-) used for transfections displayed good colloidal stability, with a hydrodynamic diameters of ≈ 150 nm and an overall surface charges of ≈ +30 mV. DNA/4A4Hex-calix-AGs nanoassemblies, everyone tested at the optimal CR, invariably showed good transfection efficiency in two cell lines, along with low-to-negligible cytotoxicity. Besides, DNA/4A4Hex-calix-calix-AG complexes exhibited appreciable antimicrobial activity against Gram-negative bacteria, even greater than uncomplexed 4A4Hex-calix-calix-AGs. Altogether, these results disclose 4A4Hex-calix-AGs as promising gene delivery tools with unique antibacterial properties.
- Beta-lactam carryover in arterial and central venous catheters is negligible. [Journal Article]
- CCClin Chim Acta 2018 Aug 14
- CONCLUSIONS: Carryover from prior infusions does not appear to jeopardize measurements of piperacillin-tazobactam, meropenem, or vancomycin in commonly used vascular catheters at our institution. Caution in interpreting samples obtained for cefepime measurements appears advised until more data is available.
- Antibiotic Dosing in Sustained Low-Efficiency Dialysis in Critically Ill Patients. [Review]
- CJCan J Kidney Health Dis 2018; 5:2054358118792229
- Sustained low-efficiency dialysis (SLED) is increasingly used as a renal replacement modality in critically ill patients with acute kidney injury (AKI) and hemodynamic instability. There is, therefor...
Sustained low-efficiency dialysis (SLED) is increasingly used as a renal replacement modality in critically ill patients with acute kidney injury (AKI) and hemodynamic instability. There is, therefore, a greater need for the understanding of the antibiotic dosage and pharmacokinetics in these patients, to provide them with optimal therapy.
- Aminoglycoside ribosome interactions reveal novel conformational states at ambient temperature. [Journal Article]
- NANucleic Acids Res 2018 Aug 03
- The bacterial 30S ribosomal subunit is a primary antibiotic target. Despite decades of discovery, the mechanisms by which antibiotic binding induces ribosomal dysfunction are not fully understood. Am...
The bacterial 30S ribosomal subunit is a primary antibiotic target. Despite decades of discovery, the mechanisms by which antibiotic binding induces ribosomal dysfunction are not fully understood. Ambient temperature crystallographic techniques allow more biologically relevant investigation of how local antibiotic binding site interactions trigger global subunit rearrangements that perturb protein synthesis. Here, the structural effects of 2-deoxystreptamine (paromomycin and sisomicin), a novel sisomicin derivative, N1-methyl sulfonyl sisomicin (N1MS) and the non-deoxystreptamine (streptomycin) aminoglycosides on the ribosome at ambient and cryogenic temperatures were examined. Comparative studies led to three main observations. First, individual aminoglycoside-ribosome interactions in the decoding center were similar for cryogenic versus ambient temperature structures. Second, analysis of a highly conserved GGAA tetraloop of h45 revealed aminoglycoside-specific conformational changes, which are affected by temperature only for N1MS. We report the h44-h45 interface in varying states, i.e. engaged, disengaged and in equilibrium. Third, we observe aminoglycoside-induced effects on 30S domain closure, including a novel intermediary closure state, which is also sensitive to temperature. Analysis of three ambient and five cryogenic crystallography datasets reveal a correlation between h44-h45 engagement and domain closure. These observations illustrate the role of ambient temperature crystallography in identifying dynamic mechanisms of ribosomal dysfunction induced by local drug-binding site interactions. Together, these data identify tertiary ribosomal structural changes induced by aminoglycoside binding that provides functional insight and targets for drug design.
- [Changes of the auditory function in he children with chronic kidney failure]. [Journal Article]
- VOVestn Otorinolaringol 2018; 83(4):56-59
- The risk factors that contribute to the development of hearing loss in the children with chronic kidney failure (CRF) are complications and/or manifestations of the disease itself as well as the side...
The risk factors that contribute to the development of hearing loss in the children with chronic kidney failure (CRF) are complications and/or manifestations of the disease itself as well as the side effects of its treatment. There are many similarities between the anatomical, physiological, and pharmacological features of the nephron and the striavascularis of the cochlea. The objective of the present study was the evaluation of the status of the auditory function in the children presenting with CRF.
- Aminoglycoside Heteroresistance in Acinetobacter baumannii AB5075. [Journal Article]
- MmSphere 2018 Aug 15; 3(4)
- Heteroresistance is a phenomenon where a subpopulation of cells exhibits higher levels of antibiotic resistance than the general population. Analysis of tobramycin resistance in Acinetobacter baumann...
Heteroresistance is a phenomenon where a subpopulation of cells exhibits higher levels of antibiotic resistance than the general population. Analysis of tobramycin resistance in Acinetobacter baumannii AB5075 using Etest strips demonstrated that colonies with increased resistance arose at high frequency within the zone of growth inhibition. The presence of a resistant subpopulation was confirmed by population analysis profiling (PAP). The tobramycin-resistant subpopulation was cross resistant to gentamicin but not amikacin. The increased tobramycin resistance phenotype was highly unstable, and cells reverted to a less resistant population at frequencies of 60 to 90% after growth on nonselective media. Furthermore, the frequency of the resistant subpopulation was not increased by preincubation with subinhibitory concentrations of tobramycin. The tobramycin-resistant subpopulation was shown to replicate during the course of antibiotic treatment, demonstrating that these were not persister cells. In A. baumannii AB5075, a large plasmid (p1AB5075) carries aadB, a 2″-nucleotidyltransferase that confers resistance to both tobramycin and gentamicin but not amikacin. The aadB gene is part of an integron and is carried adjacent to four additional resistance genes that are all flanked by copies of an integrase gene. In isolates with increased resistance, this region was highly amplified in a RecA-dependent manner. However, in a recA mutant, colonies with unstable tobramycin resistance arose by a mechanism that did not involve amplification of this region. These data indicate that tobramycin heteroresistance occurs by at least two mechanisms in A. baumannii, and future studies to determine its effect on patient outcomes are warranted.IMPORTANCEAcinetobacter baumannii has become an important pathogen in hospitals worldwide, where the incidence of these infections has been increasing. A. baumannii infections have become exceedingly difficult to treat due to a rapid increase in the frequency of multidrug- and pan-resistant isolates. This has prompted the World Health Organization to list A. baumannii as the top priority for the research and development of new antibiotics. This study reports for the first time a detailed analysis of aminoglycoside heteroresistance in A. baumannii We define the mechanistic basis for heteroresistance, where the aadB(ant2″)Ia gene encoding an aminoglycoside adenylyltransferase becomes highly amplified in a RecA-dependent manner. Remarkably, this amplification of 20 to 40 copies occurs stochastically in 1/200 cells in the absence of antibiotic selection. In addition, we provide evidence for a second RecA-independent mechanism for aminoglycoside heteroresistance. This study reveals that aminoglycoside resistance in A. baumannii is far more complex than previously realized and has important implications for the use of aminoglycosides in treating A. baumannii infections.
- Effects of guanidino modified aminoglycosides on mammalian membranes studied using a quartz crystal microbalance. [Journal Article]
- MMedchemcomm 2017 May 01; 8(5):1112-1120
- The increase in bacterial and viral resistance to current therapeutics has led to intensive research for new antibacterial and antiviral agents. Among these, aminoglycosides and their guanidino deriv...
The increase in bacterial and viral resistance to current therapeutics has led to intensive research for new antibacterial and antiviral agents. Among these, aminoglycosides and their guanidino derivatives are potent candidates targeting specific RNA sequences. It is necessary that these substances can pass across mammalian membranes in order to reach their intracellular targets. This study investigated the effects of the aminoglycosides kanamycin A and neomycin B and their guanidino derivatives on mammalian mimetic membranes using a quartz crystal microbalance with dissipation monitoring (QCM-D). Lipid bilayers as membrane models were deposited onto gold coated quartz crystals and aminoglycosides added afterwards. Notably, the guanidino derivatives exhibited an initial stiffening of the membrane layer indicating a quick insertion of the planar guanidino groups into the membrane. The guanidino derivatives also reached their maximum binding to the membrane at lower concentrations than the native compounds. Therefore, these modified aminoglycosides are promising agents for the development of new antimicrobial treatments.
- Exploring eukaryotic versus prokaryotic ribosomal RNA recognition with aminoglycoside derivatives. [Journal Article]
- MMedchemcomm 2018 Mar 01; 9(3):503-508
- New derivatives of aminoglycosides containing 6'-carboxylic acid or 6'-amide on their ring I were designed, synthesized and their ability to readthrough nonsense mutations was examined in vitro, alon...
New derivatives of aminoglycosides containing 6'-carboxylic acid or 6'-amide on their ring I were designed, synthesized and their ability to readthrough nonsense mutations was examined in vitro, along with the protein translation inhibition in prokaryotic and eukaryotic systems. The observed structure-activity relationships, along with the comparative molecular dynamics simulations within the eukaryotic rRNA decoding site, showed high sensitivity of 6'-position to substitution, indicating that the rational design of potent stop-codon read-through inducers requires consideration of not only the structure and energetics of the drug-RNA interaction but also the dynamics associated with that interaction.
- Pharmacokinetic evaluation of meropenem and vaborbactam for the treatment of urinary tract infection. [Journal Article]
- EOExpert Opin Drug Metab Toxicol 2018 Aug 14
- Meropenem/vaborbactam (M/V) represents the first carbapenem and β-lactamase inhibitor combination approved for treatment of cUTI, including pyelonephritis. Vaborbactam is a novel boronic acid, β-lact...
Meropenem/vaborbactam (M/V) represents the first carbapenem and β-lactamase inhibitor combination approved for treatment of cUTI, including pyelonephritis. Vaborbactam is a novel boronic acid, β-lactamase inhibitor with a high affinity for serine β-lactamases, including Klebsiella pneumoniae carbapenemase (KPC). This combination, Vabomere™, was approved in August 2017 by the United States Food and Drug Administration (FDA) for the treatment of complicated urinary tract infections (cUTI) in patients 18 years or older, including pyelonephritis, caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae species complex. Areas covered: Relevant literature regarding microbiology, pharmacokinetics, pharmacodynamics, and clinical trials evaluating efficacy, safety and tolerability will be discussed. Expert opinion: Current treatment options for KPC-producing infections such as aminoglycosides, polymyxins, fosfomycin, and tigecycline are associated with concerns regarding efficacy, toxicities, optimal dosing, and/or development of resistance. Additionally, resistance to the new combination product of ceftazidime/avibactam has also emerged. Current clinical evidence supporting the use of M/V for KPC-producing infections is limited to an open-label, randomized, phase 3 study in a small number of patients with serious infections due to carbapenem-resistant Enterobacteriaceae. Although M/V is not approved for KPC-producing infections, we believe that M/V will become a preferred agent for KPC-producing Enterobacteriaceae infections.
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- Activity of plazomicin in combination with other antibiotics against multidrug-resistant Enterobacteriaceae. [Journal Article]
- DMDiagn Microbiol Infect Dis 2018 Jul 11
- Plazomicin is a next-generation aminoglycoside that was approved by the US FDA in June 2018 for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis due to Escheric...
Plazomicin is a next-generation aminoglycoside that was approved by the US FDA in June 2018 for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis due to Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae and Proteus mirabilis. Plazomicin is active against multi-drug resistant (MDR) Enterobacteriaceae, where combination therapy is often used to treat infections caused by these pathogens. To determine synergy with other antibiotics, plazomicin was combined with antibiotics in checkerboard assays against MDR Enterobacteriaceae, including isolates with resistance to aminoglycosides and β-lactams; 10 Escherichia coli isolates, 8 Klebsiella spp. isolates, 10 Enterobacter spp. isolates, and 2 Citrobacter freundii isolates were evaluated. Plazomicin had potent activity against MDR Enterobacteriaceae, including aminoglycoside-resistant strains, with MIC ranges of 0.5 - 2 μg/mL against E. coli isolates, 0.12 - 8 μg/mL against Klebsiella spp. isolates, 0.25 - 2 μg/mL against Enterobacter spp. isolates, and 0.06 - 0.25 μg/mL against C. freundii isolates. Synergy between plazomicin and piperacillin/tazobactam or ceftazidime was observed by checkerboard studies and confirmed by time-kill assays. No combination showed antagonism. These studies indicate that plazomicin has potential as a monotherapy and as combination therapy for treating serious Gram-negative infections caused by MDR Enterobacteriaceae.