Exploring Structure-Activity Relationships of Niclosamide-Based Colistin Potentiators in Colistin-Resistant Gram-Negative Bacteria.

Colistin is primarily used as a last resort antibiotic against highly resistant Gram-negative bacteria (GNB). Rising rates of colistin resistance, however, may limit future use of this agent. The anthelmintic drug niclosamide has been shown to enhance colistin activity in combination therapy, but a detailed structure-activity relationship (SAR) for niclosamide against GNB has yet to be studied. A series of niclosamide analogs were synthesized to perform an SAR, leading to the discovery of a lead compound that displayed comparable colistin-potentiating activity to niclosamide with reduced cytotoxicity. Overall, this work provides important insights into synthetic strategies for the future development of new niclosamide derivatives and demonstrates that toxicity to mammalian cells can be reduced while maintaining colistin potentiation.

Amphiphilic tribasic galactosamines potentiate rifampicin in Gram-negative bacteria at low Mg++/Ca++concentrations.

Many antibiotics specific to Gram-positive bacteria like rifampicin (RIF) are inactive in Gram-negative bacteria because of outer membrane (OM) impermeability. Enhancing the OM permeability of these antibiotics with the help of OM perturbants is a promising strategy to develop new agents against Gram-negative bacteria. Here we report the synthesis and biological properties of amphiphilic tribasic galactosamines as potential RIF potentiators. Our results demonstrate that tribasic galactose-based amphiphiles potentiate RIF in multidrug-resistant Acinetobacter baumannii and Escherichia coli but not Pseudomonas aeruginosa in low salt-containing media. Under these conditions, lead compounds 20, 22 and 35 lowered the minimum inhibitory concentration of RIF by 64- to 256-fold against Gram-negative bacteria. However, the RIF-potentiating effect was reduced when bivalent Mg++ or Ca++ ions were added in the media at physiological concentrations. Overall, our results indicate that amphiphilic tribasic galactosamine-based compounds show reduced RIF-potentiating effects when compared to amphiphilic tobramycin antibiotics at physiological salt concentrations.

TiO2-guanine as a new amalgamation compound for fabrication of a disposable biosensor with high sensitivity and rapid detection of H1N1 swine flu virus.

A TiO2-guanine nanocomposite (TG NC)-based electrochemical biosensor was immobilized with hemagglutinin (HA) gene specific probe with 5' NH2 group on screen-printed gold electrode (probe(ss)DNA-TG-SPGE). The modified biosensor was examined for H1N1 swine flu virus. TG NCs along with precursors were characterized spectroscopically and morphologically by employing several approaches. Electrochemical investigations were performed with the help of cyclic voltammetric (CV) and electrochemical impedance spectroscopy (EIS) in 0.1 M phosphate buffer saline (PBS; pH 7.4) with 1 µM methylene blue (MB) redox indicator. For better detection of single-stranded virus DNA, the modified electrode was optimized at various concentrations, pH, and scan rates. The modified biosensor showed high sensitivity (40.32 µA/ng.cm2), low LOD (0.00024 ng/6 µL), and broad linear range 0.0002-20 ng/6µL with coefficient of determination of R2=0.9981 for H1N1 virus detection. The HA gene-modified biosensor presented decent stability and specificity against different infectious pathogens including H3N2 virus and human DNA with negative response. Furthermore, the modified biosensor also responded well for real sample target DNA detection with a recovery of >96%. The simply designed HA gene-modified biosensor transduces decreased current response towards target-specific (ss)DNA binding and could be used as a rapid detection tool for H1N1 swine flu virus diagnosis.

Trimeric Tobramycin/Nebramine Synergizes ß-Lactam Antibiotics against Pseudomonas aeruginosa.

ß-Lactam antibiotics remain one of the most effective therapeutics to treat infections caused by Gram-negative bacteria (GNB). However, since ancient times, bacteria have developed multiple resistance mechanisms toward this class of antibiotics including overexpression of ß-lactamases, suppression of porins, outer membrane impermeability, overexpression of efflux pumps, and target modifications. To cope with these challenges and to extend the lifetime of existing ß-lactam antibiotics, ß-lactamase inhibitors are combined with ß-lactam antibiotics to prevent antibiotic inactivation by ß-lactamases. The combination therapy of an outer membrane permeabilizer with ß-lactam antibiotics is an alternative approach to overcoming bacterial resistance of ß-lactams in GNB. This approach is of particular interest for pathogens with highly impermeable outer membranes like Pseudomonas aeruginosa. Previous studies have shown that outer membrane permeabilizers can be designed by linking tobramycin and nebramine units together in the form of dimers or chimeras. In this study, we developed trimeric tobramycin and nebramine-based outer membrane permeabilizers presented on a central 1,3,5-triazine framework. The resultant trimers are capable of potentiating outer membrane-impermeable antibiotics but also ß-lactams and ß-lactam/ß-lactamase inhibitor combinations against resistant P. aeruginosa isolates. Furthermore, the microbiological susceptibility breakpoints of ceftazidime, aztreonam, and imipenem were reached by a triple combination consisting of an outer-membrane permeabilizer/ß-lactam/ß-lactamase inhibitor in ß-lactam-resistant P. aeruginosa isolates. Overall, our results indicate that trimeric tobramycins/nebramines can rescue clinically approved ß-lactams and ß-lactam/ß-lactamase inhibitor combinations from resistance.

Guanidinylated Amphiphilic Tobramycin Derivatives Synergize with ß-Lactam/ß-Lactamase Inhibitor Combinations against Pseudomonas aeruginosa.

Carbapenem-resistant Pseudomonas aeruginosa (P. aeruginosa) was designated as a critical priority pathogen by the World Health Organization for which new therapeutic solutions are required. With the rapid dissemination of ß-lactamases in P. aeruginosa, ß-lactam (BL) antibiotics are used in conjunction with ß-lactamase inhibitors (BLI). The effectiveness of the BL/BLI combination could be further enhanced with the inclusion of an outer membrane (OM) permeabilizer, such as aminoglycosides and aminoglycoside-based adjuvants. Thus, the development of seven tobramycin derivatives reported herein focused on improving OM permeabilizing capabilities and reducing associated toxicity. The structure-activity relationship studies emphasized the effects of the nature of the cationic group; the number of polar head groups and positive charges; and flexibility, length, and steric bulk of the hydrophobic moiety. The optimized guanidinylated tobramycin-biphenyl derivative was noncytotoxic and demonstrated the ability to potentiate ceftazidime and aztreonam monotherapy and in dual combinations with avibactam against multidrug-resistant (MDR) and ß-lactamase harboring isolates of P. aeruginosa. The triple combination of ceftazidime/avibactam plus guanidinylated tobramycin-biphenyl resulted in rapid bactericidal activity within 4-8 h of treatment, demonstrating the potential application of these guanidinylated amphiphilic tobramycin derivatives in augmenting BL/BLI combinations.

Exploring Antibiotic-Potentiating Effects of Tobramycin-Deferiprone Conjugates in Pseudomonas aeruginosa.

Metal ions, including Fe3+, affect the target site binding of some antibiotics and control the porin- and siderophore-mediated uptake of antibiotics. Amphiphilic tobramycins are an emerging class of antibiotic potentiators capable of synergizing with multiple classes of antibiotics against Gram-negative bacteria, including Pseudomonas aeruginosa. To study how the antibiotic-potentiating effect of amphiphilic tobramycins is affected by the presence of intermolecular iron chelators, we conjugated the FDA-approved iron chelator deferiprone (DEF) to tobramycin (TOB). Three TOB-DEF conjugates differing in the length of the carbon tether were prepared and tested for antibacterial activity and synergistic relationships with a panel of antibiotics against clinical isolates of P. aeruginosa. While all TOB-DEF conjugates were inactive against P. aeruginosa, the TOB-DEF conjugates strongly synergized with outer-membrane-impermeable antibiotics, such as novobiocin and rifampicin. Among the three TOB-DEF conjugates, 1c containing a C12 tether showed a remarkable and selective potentiating effect to improve the susceptibility of multidrug-resistant P. aeruginosa isolates to tetracyclines when compared with other antibiotics. However, the antibacterial activity and antibiotic-potentiating effect of the optimized conjugate was not enhanced under iron-depleted conditions, indicating that the function of the antibiotic potentiator is not affected by the Fe3+ concentration.

Ppy/TiO2-SiO2 nanohybrid series: synthesis, characterization, photocatalytic activity, and antimicrobial potentiality.

A series of polypyrrole doped TiO2-SiO2 nanohybrids (Ppy/TS NHs) were synthesized thru in-situ oxidation polymerization by varying weight ratio of pyrrole. The structural analysis of NHs were characterized by X-ray Diffraction (XRD) spectra, UV-visible (UV-Vis) spectra and X-ray Photoelectron spectra (XPS) confirmed synthesis of nanomaterials. Surface and morphological study done by adopting, Scanning Electron Microscopy (SEM), Energy Dispersive Spectroscopy (EDS), Transmittance Electron Microscopy (TEM) and Brunauer-Emmett-Teller (BET) analysis confirmed the homogenous distribution, nano range size formation and mesoporous nature of nanohybrids. Further, electrochemical behavior of synthesized NHs investigated by adopting Electrochemical Impedance Spectroscopy (EIS) showed good kinetic behaviour and electron transport tendency. The nanohybrids and precursors were examined for photocatalytic degradation of methylene blue (MB) dye and revealed enhanced degradation tendency for the NHs series photocatalysts. It was found that variation of pyrrole (0.1 to 0.3 g) to TS nanocomposites (TS Nc) increased the photocatalytic potential of TS Nc. The maximum photodegradation efficacy was found to be 90.48% in 120 min for Ppy/TS0.2 NHs under direct solar light. Additionally, Ppy/TS0.2 NHs performed appreciably towards antibacterial studies against some Gram-positive and Gram-negative deleterious bacteria, Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Shigella flexneri microbes.

In-situ composited g-C3N4/polypyrrole nanomaterial applied as energy-storing electrode with ameliorated super-capacitive performance.

Graphitic carbon nitride (g-C3N4) and polypyrrole (ppy) nanocomposites are synthesized and cast off as material for electrodes intended for energy storage, where the amount of pyrrole is being kept static after optimization by altering the amount of g-C3N4 to make a series of g-C3N4/ppy (pcn) nanocomposites. These nanocomposites are successfully synthesized by employing in-situ oxidation polymerization by oxidizing pyrrole. The nanocomposites are further characterized by Fourier transform infrared spectroscopy (FT-IR) for structural investigation, thermal gravimetric analysis (TGA) for thermal stability analysis, and field emission scanning electron microscopy (FESEM) and transmission electron microscopy (HR-TEM) for surface morphological scrutiny. The electrochemical measurements of the series are inspected with the help of galvanostatic charge-discharge (GCD), electrochemical impedance spectroscopy (EIS), and cyclic voltammetry (CV) measurements. It is detected that 0.4 pcn has the highest specific capacitance value of 555 F g-1 at 10 mV s-1 scan rate through CV and 475 F g-1 at a current density of 0.5 A g-1 through GCD in 1 M H2SO4 in contrast with neat g-C3N4 as well as ppy where both the precursors have this value below 100 F g-1. This composite exhibited good cyclic stability with high retention. The high energy density of 0.4 pcn composite is analyzed at 86 Wh/kg at a power density of 300 W/kg. Due to facile synthesis, significant specific capacitance, and excellent energy density, pcn is a promising candidate for its application in energy storage purposes.

An eco-friendly corrosion inhibitor Cuscuta reflexa extract and PEG400 for mild steel inhibition in acidic medium: computational and experimental investigations.

Herein, the mechanism of corrosion prevention of mild steel (MS) by extract of Cuscuta reflexa/Amarbel (AME) as green inhibitor is explained by gravitational, electrochemical measurements. The viability of neat extract and after adding an intensifier was investigated as corrosion inhibitor for MS in hydrochloric acid. The presence of electron-rich moieties in AME was characterized through Fourier-transform infrared spectroscopy (FTIR). Furthermore, polarization measurements showed that AME acted as a mixed type inhibitor against corrosion. The formulation of 100 ppm AME with 50 ppm polyethylene glycol 400 (PEG400) as an intensifier showed inhibition efficiency of 97.51% for MS in 0.5 M HCl. The protection of MS in (AME + PEG) formulation was also assessed through the Langmuir, Freundlich, and Flory-Huggins adsorption isotherm model. The surface studies of the MS were examined by atomic force microscopy (AFM) and scanning electron microscopy (SEM) that indicated a smoothened surface of the metal in the presence of the studied compounds. XPS study was executed to analyze the interaction of the inhibitor with the metal surface. In addition, computational quantum study provides the molecular structural relationship with corrosion inhibitive competence of the extract.

The Potential of Novel Lipid Agents for the Treatment of Chemotherapy-Resistant Human Epithelial Ovarian Cancer.

Recurrent epithelial ovarian cancer (EOC) coincident with chemotherapy resistance remains the main contributor to patient mortality. There is an ongoing investigation to enhance patient progression-free and overall survival with novel chemotherapeutic delivery, such as the utilization of antiangiogenic medications, PARP inhibitors, or immune modulators. Our preclinical studies highlight a novel tool to combat chemotherapy-resistant human EOC. Glycosylated antitumor ether lipids (GAELs) are synthetic glycerolipids capable of killing established human epithelial cell lines from a wide variety of human cancers, including EOC cell lines representative of different EOC histotypes. Importantly, GAELs kill high-grade serous ovarian cancer (HGSOC) cells isolated from the ascites of chemotherapy-sensitive and chemotherapy-resistant patients grown as monolayers of spheroid cultures. In addition, GAELs were well tolerated by experimental animals (mice) and were capable of reducing tumor burden and blocking ascites formation in an OVCAR-3 xenograft model. Overall, GAELs show great promise as adjuvant therapy for EOC patients with or without chemotherapy resistance.

Urine and serum fetuin-A levels in patients with urolithiasis.

INTRODUCTION: Fetuin-A is a glycoprotein secreted by liver and has been shown to inhibit extraosseous mineralization. Urolithiasis may be a manifestation in the urinary tract due to fetuin deficiency in urine. The objective of this study was to compare the 24-h urine and serum fetuin-A levels of patients with and without urolithiasis. METHODS: Serum and 24-h urine fetuin-A levels were measured in 41 patients with bilateral, multiple, or recurrent urinary tract calculi (Group A) and 41 matched controls with no calculi (Group B). Fetuin levels were measured by enzyme linked immunosorbent assay. Serum and urine fetuin-A levels in the two groups were compared. RESULTS: The median (range) 24-h urine fetuin-A value in Group A was 11.9 (1.12-221) mg/day and in Group B was 37.7 (1.28-125) mg/day. This difference was statistically significant (Mann-Whitney test, P = 0.0169). The median (range) serum fetuin-A in Group A was 0.67 (0.05-2.68) g/L and in Group B was 0.99 (0.01-5.5) g/L. The difference between serum values in the two arms was not statistically significant (Mann-Whitney test, P = 0.1817). However, the serum creatinine-adjusted mean log serum fetuin and urine fetuin were significantly different in the two arms (P = 0.003). The mean ± standard deviation (range) serum creatinine in Group A was 0.98 ± 0.25 (0.56-1.58) mg% and in Group B was 0.83 ± 0.16 (0.58-1.18) mg% (two sample t-test, P = 0.0031). CONCLUSIONS: Patients with urolithiasis have lower urine fetuin-A and creatinine-adjusted serum fetuin-A levels.

Autonomous Rubidium Clock Weak Frequency Jump Detector for Onboard Navigation Satellite System.

Frequency jumps are common in rubidium frequency sources. They affect the estimation of user position in navigational satellite systems. These jumps must be detected and corrected immediately as they have direct impact on the navigation system integrity. A novel weak frequency jump detector is proposed based on a Kalman filter with a multi-interval approach. This detector can be applied for both "sudden" and "slow" frequency transitions. In this detection method, noises of clock data are reduced by Kalman filtering, for accurate estimation of jump size with less latency. Analysis on in-orbit rubidium atomic frequency standard (RAFS) phase telemetry data shows that the detector can be used for fast detection and correction of weak frequency jumps. Furthermore, performance comparison of different existing frequency jump detection techniques with the proposed detector is discussed. A multialgorithm-based strategy is proposed depending on the jump size and latency for onboard navigation satellites having RAFS as the primary frequency source.

Vesicourethral fistula after retrograde primary endoscopic realignment in posterior urethral injury.

A 22-year-old male patient presented with iatrogenic vesicourethral fistula after immediate retrograde endoscopic realignment of urethra after a posterior urethral injury associated with pelvic fracture.