Auranofin Releasing Antibacterial and Antibiofilm Polyurethane Intravascular Catheter Coatings

Intravascular catheter related bloodstream infections (CRBSIs) are a leading cause of hospital-acquired infections worldwide, resulting not only in the burden of cost and morbidity for patients but also in the over-consumption of medical resources for hospitals and health care organizations. In this study, a novel auranofin releasing antibacterial and antibiofilm polyurethane (PU) catheter coating was developed and investigated for future use in preventing CRBSIs. Auranofin is an antirheumatic drug with recently identified antimicrobial properties. The drug carrier, PU, acts as a barrier surrounding the antibacterial agent, auranofin, to extend the drug release profile and improve its long-term antibacterial and antibiofilm efficacy and potentially the length of catheter implantation within a patient. The PU+auranofin coatings developed here were found to be highly stretchable (exhibiting ~500% percent elongation), which is important for the compliance of the material on a flexible catheter. PU+auranofin coated catheters were able to inhibit the growth of methicillin-resistant Staphylococcus aureus (MRSA) for 8 to 26 days depending on the specific drug concentration utilized during the dip coating process. The PU+auranofin coated catheters were also able to completely inhibit MRSA biofilm formation in vitro, an effect that was not observed with auranofin or PU alone. Lastly, these coatings were found to be hemocompatible with human erythrocytes and maintain liver cell viability

Gold complex compounds that inhibit drug-resistant Staphylococcus aureus by targeting thioredoxin reductase

IntroductionThere is a significant need for new antimicrobial compounds that are effective against drug-resistant microbes. Thioredoxin reductase (TrxR) is critical in redox homeostasis and was identified as a potential drug target and confirmed through inhibition by compounds auranofin and Bay11-7085.MethodsAdditional TrxR inhibitors were designed and found to exhibit antimicrobial activity against Gram-positive (Enterococcus faecium and Staphylococcus aureus) and glutathione-deficient bacteria (Helicobacter pylori). Investigational compounds were tested for antimicrobial activity, anti-biofilm efficacy, target impact, and cytotoxicity.ResultsThe first-generation molecules AU1 and AU5 inhibited TrxR activity and inhibited methicillin-resistant S. aureus strain MW2 with minimal inhibitory concentrations (MIC) of 0.125 and 0.5 μg/mL, respectively. In an S. aureus enzymatic assay, AU1 inhibited TrxR enzymatic activity in a dose-dependent manner causing a decrease in intracellular free thiols. In addition, biofilm studies demonstrated that AU1 and AU5 reduced biofilm formation at 1X MIC and disrupted mature biofilms at 4X MIC. Cytotoxicity profiles were created using human cell lines and primary cells with LD50 exceeding MICs by at least 12X.DiscussionThus, AU1 and AU5 were TrxR inhibitors that yielded low-concentration antimicrobial activity impacting S. aureus in planktonic and biofilm forms with limited toxic liability

Activity of a novel protonophore against methicillin-resistant Staphylococcus aureus

Aim: Compound 1-(4-chlorophenyl)-4,4,4-trifluoro-3-hydroxy-2-buten-1-one (compound 1) was identified as a hit against methicillin-resistant Staphylococcus aureus (MRSA) strain MW2. Methods & results: The MIC of compound 1 against MRSA was 4 μg/ml. The compound showed enhanced activity at acidic pH by lowering bacterial intracellular pH and exhibited no lysis of human red blood cells at up to 64 μg/ml and its IC50 against HepG2 cells was 32 μg/ml. The compound reduced 1-log10 colony forming units of intracellular MRSA in macrophages and prolonged the survival of MRSA-infected Caenorhabditis elegans (p = 0.0015) and Galleria mellonella (p = 0.0002). Conclusion: Compound 1 is a protonophore with potent in vitro and in vivo activity against MRSA and no toxicity in mammalian cells up to 8 μg/ml that warrants further investigation as a novel antibacterial

Antibacterial Properties of Four Novel Hit Compounds from a Methicillin-Resistant Staphylococcus aureus-Caenorhabditis elegans High-Throughput Screen

There is an urgent need for the discovery of effective new antimicrobial agents to combat the rise of bacterial drug resistance. High-throughput screening (HTS) in whole-animal infection models is a powerful tool for identifying compounds that show antibacterial activity and low host toxicity. In this report, we characterize the activities of four novel antistaphylococcal compounds identified from an HTS campaign conducted using Caenorhabditis elegans nematodes infected with methicillin-resistant Staphylococcus aureus (MRSA). The hit compounds included an Nhydroxy indole-1, a substituted melamine derivative-2, N-substituted indolic alkyl isothiocyanate-3, and pdifluoromethylsulfide analog-4 of the well-known protonophore carbonyl cyanide m-chlorophenyl hydrazone. Minimal inhibitory concentrations (MICs) of the four compounds ranged from 2 to 8 μg/ml against MRSA-MW2 and Enterococcus faecium and all were bacteriostatic. The compounds were mostly inactive against Gram-negative pathogens, with only 1 and 4 showing slight activity (MIC= 32 μg/ml) against Acinetobacter baumanii. Compounds 2 and 3 (but not 1 or 4) were found to perturb MRSA membranes. In phagocytosis assays, compounds 1, 2, and 4 inhibited the growth of internalized MRSA in macrophages, whereas compound 3 showed a remarkable ability to clear intracellular MRSA at its MIC ( p \u3c 0.001). None of the compounds showed hemolytic activity at concentrations below 64 μg/ml ( p = 0.0021). Compounds 1, 2, and 4 (but not 3) showed synergistic activity against MRSA with ciprofloxacin, while compound 3 synergized with erythromycin, gentamicin, streptomycin, and vancomycin. In conclusion, we describe four new antistaphylococcal compounds that warrant further study as novel antibacterial agents against Gram-positive organisms

Characterization of five novel anti-mrsa compounds identified using a whole-animal caenorhabditis elegans/galleria mellonella sequential-screening approach

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. There is a significant need to combat the growing challenge of antibacterial drug resistance. We have previously developed a whole-animal dual-screening platform that first used the nematode Caenorhabditis elegans, to identify low-toxicity antibacterial hits in a high-throughput format. The hits were then evaluated in the wax moth caterpillar Galleria mellonella infection model to confirm efficacy and low toxicity at a whole animal level. This multi-host approach is a powerful tool for revealing compounds that show antibacterial effects and relatively low toxicity at the whole organism level. This paper reports the use of the multi-host approach to identify and validate five new anti-staphylococcal compounds: (1) 4,4′,4”-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol(PPT), (2) (1S,2S)-2-[2-[[3-(1H-benzimidazol-2-yl)propyl]methylamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-(1-methylethyl)-2-naphthalenyl cyclopropanecarboxylate dihydrochloride(NNC), (3) 4,5,6,7-tetrabromobe nzotriazole (TBB), (4) 3-[2-[2-chloro-4-[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy] phenyl]ethenyl] benzoic acid(GW4064), and (5) N-(cyclopropylmethoxy)-3,4,5-trifluoro-2-[(4-iodo-2-methylphenyl)amino] benzamide(PD198306). The compounds reduced the severity of methicillin-resistant Staphylococcus aureus (MRSA, strain MW2) infections in both C. elegans and G. mellonella and showed minimal inhibitory concentrations (MICs) in the range of 2–8 µg/mL. Compounds NNC, PPT, and TBB permeabilized MRSA-MW2 cells to SYTOX green, suggesting that they target bacterial membranes. Compound TBB showed synergistic activity with doxycycline and oxacillin against MRSA-MW2, and compounds PPT, NNC, GW4064, and PD198306 synergized with doxycycline, polymyxin-B, gentamicin, and erythromycin, respectively. The study demonstrates the utility of the multi-host approach with follow-up hit characterization for prioritizing anti-MRSA compounds for further evaluation

Analysis of genetic diversity and population structure of Magnaporthe grisea, the causal agent of foxtail millet blast using microsatellites

Foxtail millet blast caused by Magnaporthe grisea is becoming a severe problem in foxtail millet growing regions of India. The genetic diversity and population structure of foxtail millet infecting M. grisea is crucial for developing effective management strategies, such as breeding blast-resistant cultivars. We analyzed thirty-two M. grisea isolates from ten foxtail millet-growing districts in Tamil Nadu, India for genetic diversity using twenty-nine microsatellite or simple sequence repeat (SSR) markers. A total of 103 alleles were identified with a mean of 3.55 alleles/locus. Gene diversity ranged from 0.170 to 0.717, while major allelic frequencies ranged from 0.344 to 0.906. The polymorphism information content (PIC) ranged from 0.155 to 0.680, with a mean value of 0.465. Population structure analysis of the genomic data sets revealed two major populations (SP1 and SP2) with different levels of ancestral admixture among the 32 blast isolates. Phylogenetic analysis classified the isolates into three major clusters. Analysis of molecular variance (AMOVA) showed high genetic variation among individuals and less among populations. Principal Coordinate Analysis (PCoA) revealed 27.16% genetic variation among populations. The present study provides the first report on the genetic diversity and population structure of the foxtail millet-infecting M. grisea population in Tamil Nadu, which could be useful for the development of blast-resistant foxtail millet cultivars

Halogen-Based 17β-HSD1 Inhibitors: Insights from DFT, Docking, and Molecular Dynamics Simulation Studies

The high expression of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) mRNA has been found in breast cancer tissues and endometriosis. The current research focuses on preparing a range of organic molecules as 17β-HSD1 inhibitors. Among them, the derivatives of hydroxyphenyl naphthol steroidomimetics are reported as one of the potential groups of inhibitors for treating estrogen-dependent disorders. Looking at the recent trends in drug design, many halogen-based drugs have been approved by the FDA in the last few years. Here, we propose sixteen potential hydroxyphenyl naphthol steroidomimetics-based inhibitors through halogen substitution. Our Frontier Molecular Orbitals (FMO) analysis reveals that the halogen atom significantly lowers the Lowest Unoccupied Molecular Orbital (LUMO) level, and iodine shows an excellent capability to reduce the LUMO in particular. Tri-halogen substitution shows more chemical reactivity via a reduced HOMO–LUMO gap. Furthermore, the computed DFT descriptors highlight the structure–property relationship towards their binding ability to the 17β-HSD1 protein. We analyze the nature of different noncovalent interactions between these molecules and the 17β-HSD1 using molecular docking analysis. The halogen-derived molecules showed binding energy ranging from −10.26 to −11.94 kcal/mol. Furthermore, the molecular dynamics (MD) simulations show that the newly proposed compounds provide good stability with 17β-HSD1. The information obtained from this investigation will advance our knowledge of the 17β-HSD1 inhibitors and offer clues to developing new 17β-HSD1 inhibitors for future applications

Hand Sanitizers: A Review on Formulation Aspects, Adverse Effects, and Regulations

Hand hygiene is of utmost importance as it may be contaminated easily from direct contact with airborne microorganism droplets from coughs and sneezes. Particularly in situations like pandemic outbreak, it is crucial to interrupt the transmission chain of the virus by the practice of proper hand sanitization. It can be achieved with contact isolation and strict infection control tool like maintaining good hand hygiene in hospital settings and in public. The success of the hand sanitization solely depends on the use of effective hand disinfecting agents formulated in various types and forms such as antimicrobial soaps, water-based or alcohol-based hand sanitizer, with the latter being widely used in hospital settings. To date, most of the effective hand sanitizer products are alcohol-based formulations containing 62%–95% of alcohol as it can denature the proteins of microbes and the ability to inactivate viruses. This systematic review correlated with the data available in Pubmed, and it will investigate the range of available hand sanitizers and their effectiveness as well as the formulation aspects, adverse effects, and recommendations to enhance the formulation efficiency and safety. Further, this article highlights the efficacy of alcohol-based hand sanitizer against the coronavirus