A Review of Resistance to Polymyxins and Evolving Mobile Colistin Resistance Gene (mcr) among Pathogens of Clinical Significance.

The global rise in antibiotic resistance in bacteria poses a major challenge in treating infectious diseases. Polymyxins (e.g., polymyxin B and colistin) are last-resort antibiotics against resistant Gram-negative bacteria, but the effectiveness of polymyxins is decreasing due to widespread resistance among clinical isolates. The aim of this literature review was to decipher the evolving mechanisms of resistance to polymyxins among pathogens of clinical significance. We deciphered the molecular determinants of polymyxin resistance, including distinct intrinsic molecular pathways of resistance as well as evolutionary characteristics of mobile colistin resistance. Among clinical isolates, Acinetobacter stains represent a diversified evolution of resistance, with distinct molecular mechanisms of intrinsic resistance including naxD, lpxACD, and stkR gene deletion. On the other hand, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa are usually resistant via the PhoP-PhoQ and PmrA-PmrB pathways. Molecular evolutionary analysis of mcr genes was undertaken to show relative relatedness across the ten main lineages. Understanding the molecular determinants of resistance to polymyxins may help develop suitable and effective methods for detecting polymyxin resistance determinants and the development of novel antimicrobial molecules.

Development and Validation of Facile RP-HPLC Method for Simultaneous Determination of Timolol Maleate, Moxifloxacin Hydrochloride, Diclofenac Sodium and Dexamethasone in Plasma, Aqueous Humor and Pharmaceutical Products.

The present study aimed to develop a validated RP-HPLC method for the simultaneous determination of timolol maleate (TM), moxifloxacin hydrochloride (MOXI), diclofenac sodium (DS) and dexamethasone (DEXA) in human plasma, bovine aqueous humor and pharmaceutical preparations. The chromatographic separation was studied using the C18 column. The chromatographic conditions, such as composition, pH, the flow rate of mobile phase, the temperature of column, wavelength of absorption and injection volume of the sample, were studied. The method was validated to confirm specificity, linearity and accuracy in accordance with an International Conference on Harmonization guidelines. The optimum conditions for separation included mobile phase 0.05 M monobasic phosphate buffer: acetonitrile (65:35 v/v), pH of buffer adjusted to 6.2 and the flow rate of 1 mL/minute. The optimum temperature of the column was found to be 35°C, absorption wavelength 265 nm and injection volume 50 µL. The baseline separation of all four drugs with good sensitivity, resolution, and a less than 15 min run time was achieved. The retention time of TM, MOXI, DS and DEXA were 4.3,5.7,9.9 and 13.5 minutes respectively. The limit of detection (LOD) values were 6.2, 4.8, 0.8 and 1.2 ng/mL for TM, MOXI, DS and DEXA, respectively, whereas their respective limit of quantification (LOQ) values was: were 42.6, 26.8, 5.6 and 6.2 ng/mL. The coefficient of variation for intra-day and inter-day were in the range of 0.32-1.57 and 1.29-3.07%, respectively. The method was found to be sensitive, precise and accurate in human plasma and bovine aqueous humor and can be applied for the quantification of these compounds in plasma, aqueous humor and pharmaceuticals.

The Possible Role of Prion-Like Viral Protein Domains on the Emergence of Novel Viruses as SARS-CoV-2.

Self-replicating proteins or prions deviate from the central dogma of replication. The discovery of prion-like domains in coronavirus SARS-CoV-2 suggests their possible role in viral evolution. Here, we have outlined the possible role of self-replicating protein-like domains in the emergence of novel viruses. Further studies are needed to understand the function of these viral self-replicating protein-like domains and whether they could be antiviral target(s) for the development of effective antiviral agents in the future.

Immuno-pathogenesis of nCOVID-19 and a possible host-directed therapy including anti-inflammatory and anti-viral prostaglandin (PG J2) for effective treatment and reduction in the death toll.

Coronaviruses including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, also known as 2019-nCoV especially in China) replicate and divide in host cells. During this they are partly hidden from the innate immune responses although inflammatory consequences of viral replication still occur. We propose that anti-inflammatory antiviral prostaglandins may not only restrict viral replication but also prevent inflammatory responses in the lungs and other vital organs that are known to be part of the immuno-pathogenesis of coronavirus disease-19 (COVID-19). The combination of anti-inflammatory antiviral prostaglandins with interferons may lead to the clearance of viruses inside growth-restricted infected cells. However, further experimental studies and clinical trials should be conducted to evaluate the safety and efficacy of these possible therapies.

Identification of novel in vitro antibacterial action of cloprostenol and evaluation of other non-antibiotics against multi-drug resistant A. baumannii.

A total of 24 non-antibiotic compounds were tested for their antimicrobial activity against Escherichia coli, Klebsiella pneumoniae (ATCC) and an MDR strain of Acinetobacter baumannii using an agar well diffusion assay. To study additive effects, 100 µl of each antibiotic and 50 µl of each non-antibiotic were used. Cloprostenol was the only non-antibiotic that showed antibacterial activity against all bacterial strains. Cloprostenol had an additive antimicrobial effect with the tested antibiotics against the MDR A. baumannii strain.

Evaluation of synergistic antimicrobial effect of vitamins (A, B1, B2, B6, B12, C, D, E and K) with antibiotics against resistant bacterial strains.

OBJECTIVES: Multidrug-resistant (MDR) superbugs, including Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus (MRSA), are a challenge for healthcare professionals. In this study, the synergistic activity of vitamins with antibiotics against resistant bacterial strains was evaluated. METHODS: Synergistic effects between antibiotics and stock solutions of vitamins were evaluated by the Kirby-Bauer disk diffusion assay. Distilled water and propylene glycol were used as solvent for water-soluble and fat-soluble vitamins, respectively. Final concentrations of 10mg/mL for each water-soluble vitamin [B1 (thiamine), B2 (riboflavin), B6 (pyridoxine), B12 (methylcobalamin) and C (ascorbic acid)] and 0.1mg/mL for each fat-soluble vitamin [A (retinol), D (cholecalciferol), E (α-tocopherol) and K (menadione)] were used in combination with the antibiotics. RESULTS: The results demonstrated that vitamins K and E had good synergistic activity with piperacillin/tazobactam, imipenem and doripenem against A. baumannii, whilst vitamins B1, B2 and B12 showed remarkable synergistic activity with linezolid against MRSA. Vitamin B1 was further shown to have better synergism with oxacillin, tetracycline, rifampicin and linezolid against MRSA. The fat-soluble vitamins E and K showed good synergism against Gram-negative A. baumannii, whilst the water-soluble vitamins B1, B2 and B12 were effective against MRSA but not against A. baumannii. CONCLUSIONS: This synergistic action of vitamins with antibiotics may be used as a tool to treat MDR superbugs, with further evaluation required at a molecular level.