Activity Of Quinolones Research Articles

Footslog of a wild weed to pharmacy-a methodical review on traditional herb Euphorbia hirta linn

Euphorbia hirta is a funeral herbal medicine widely used in traditional remedies for various ailments like asthma, skin diseases, hypertension, jaundice, gonorrhea and dengue. Many researchers proposed the medicinal properties of E.hirta in various aspects. A detailed study shows the different pharmacological activities like anti-inflammatory, anti-biotic, anti-malarial, anti-bacterial and anti-ulcer efficacy. Previous studies showed that Euphorbia hirta possess the activity as like quinolone activity. Improved microcirculation and increasing capillary resistance has been achieved by the flavonoids present in this folklore herb protects gastric damage. The latex exudate has been reported for treatment of conjunctivitis as eye drops. High anti-oxidant level in this weed synergizes the therapeutic effects. This comprehensive review describes about the properties, ethno pharmacology, chemical constituents and various concepts of E hirta. Furthermore, this will paves the way for accounting the study in different angles and for the development of new lead compounds with multiple pharmacological actions.

Synergistic Effect of SOS Response and GATC Methylome Suppression on Antibiotic Stress Survival in Escherichia coli.

The suppression of the SOS response has been shown to enhance the in vitro activity of quinolones. Furthermore, Dam-dependent base methylation has an impact on susceptibility to other antimicrobials affecting DNA synthesis. Here, we investigated the interplay between these two processes, alone and in combination, in terms of antimicrobial activity. A genetic strategy was used employing single- and double-gene mutants for the SOS response (recA gene) and the Dam methylation system (dam gene) in isogenic models of Escherichia coli both susceptible and resistant to quinolones. Regarding the bacteriostatic activity of quinolones, a synergistic sensitization effect was observed when the Dam methylation system and the recA gene were suppressed. In terms of growth, after 24 h in the presence of quinolones, the Δdam ΔrecA double mutant showed no growth or delayed growth compared to the control strain. In bactericidal terms, spot tests showed that the Δdam ΔrecA double mutant was more sensitive than the ΔrecA single mutant (about 10- to 102-fold) and the wild type (about 103- to 104-fold) in both susceptible and resistant genetic backgrounds. Differences between the wild type and the Δdam ΔrecA double mutant were confirmed by time-kill assays. The suppression of both systems, in a strain with chromosomal mechanisms of quinolone resistance, prevents the evolution of resistance. This genetic and microbiological approach demonstrated the enhanced sensitization of E. coli to quinolones by dual targeting of the recA (SOS response) and Dam methylation system genes, even in a resistant strain model.

Quinolone Resistance Genes and Their Contribution to Resistance in Vibrio cholerae Serogroup O139

Quinolones are commonly used for reducing the duration of diarrhea, infection severity, and limiting further transmission of disease related to Vibrio cholerae, but V. cholerae susceptibility to quinolone decreases over time. In addition to mutations in the quinolone-resistance determining regions (QRDRs), the presence of qnr and other acquired genes also contributes to quinolone resistance. We determined the prevalence of quinolone resistance related genes among V. cholerae O139 strains isolated in China. We determined that eight strains carried qnrVC, which encodes a pentapeptide repeat protein of the Qnr subfamily, the members of which protect topoisomerases from quinolone action. Four qnrVC alleles were detected: qnrVC1, qnrVC5, qnrVC12, and qnrVC9. However, the strains carrying qnrVC1, qnrVC5, and qnrVC12 were ciprofloxacin (CIP)-sensitive. Contrastingly, the strain carrying qnrVC9 demonstrated high CIP resistance. qnrVC9 was carried by a small plasmid, which was conjugative and contributed to the high CIP resistance to the receptor V. cholerae strain. The same plasmid was also detected in V. vulnificus. The qnrVC1, qnrVC5, and qnrVC12 were cloned into expression plasmids and conferred CIP resistance on the host V. cholerae O139 strain. Our results revealed the contribution of quinolone resistance mediated by the qnrVC9 carried on the small plasmid and its active horizontal transfer among Vibrio species. The results also suggested the different effects of qnrVC alleles in different V. cholerae strains, which is possibly due to differences in sequences of qnrVC alleles and even the genetic characteristics of the host strains.

Synthesis, Characterization and Antibacterial Mechanism of Action of (Fluoro) Quinolones: An Overview

Quinolones are used to treat bacterial infections. Given their good tolerance and demonstrated activity, fluoroquinolones are widely prescribed. This wide use has unfortunately led to bacterial resistance increase. Many efforts have been made to develop new fluoroquinolone antibiotics. However, new and more effective derivatives need to be investigated. This is an overview of studies done these last decades, on fluoroquinolone synthesis, their characterization and their mechanism of actions.

Aquatic Environments as Hotspots of Transferable Low-Level Quinolone Resistance and Their Potential Contribution to High-Level Quinolone Resistance.

The disposal of antibiotics in the aquatic environment favors the selection of bacteria exhibiting antibiotic resistance mechanisms. Quinolones are bactericidal antimicrobials extensively used in both human and animal medicine. Some of the quinolone-resistance mechanisms are encoded by different bacterial genes, whereas others are the result of mutations in the enzymes on which those antibiotics act. The worldwide occurrence of quinolone resistance genes in aquatic environments has been widely reported, particularly in areas impacted by urban discharges. The most commonly reported quinolone resistance gene, qnr, encodes for the Qnr proteins that protect DNA gyrase and topoisomerase IV from quinolone activity. It is important to note that low-level resistance usually constitutes the first step in the development of high-level resistance, because bacteria carrying these genes have an adaptive advantage compared to the highly susceptible bacterial population in environments with low concentrations of this antimicrobial group. In addition, these genes can act additively with chromosomal mutations in the sequences of the target proteins of quinolones leading to high-level quinolone resistance. The occurrence of qnr genes in aquatic environments is most probably caused by the release of bacteria carrying these genes through anthropogenic pollution and maintained by the selective activity of antimicrobial residues discharged into these environments. This increase in the levels of quinolone resistance has consequences both in clinical settings and the wider aquatic environment, where there is an increased exposure risk to the general population, representing a significant threat to the efficacy of quinolone-based human and animal therapies. In this review the potential role of aquatic environments as reservoirs of the qnr genes, their activity in reducing the susceptibility to various quinolones, and the possible ways these genes contribute to the acquisition and spread of high-level resistance to quinolones will be discussed.

Peroxy Intermediate Drives Carbon Bond Activation in the Dioxygenase AsqJ.

Dioxygenases catalyze stereoselective oxygen atom transfer in metabolic pathways of biological, industrial, and pharmaceutical importance, but their precise chemical principles remain controversial. The α-ketoglutarate (αKG)-dependent dioxygenase AsqJ synthesizes biomedically active quinolone alkaloids via desaturation and subsequent epoxidation of a carbon-carbon bond in the cyclopeptin substrate. Here, we combine high-resolution X-ray crystallography with enzyme engineering, quantum-classical (QM/MM) simulations, and biochemical assays to describe a peroxidic intermediate that bridges the substrate and active site metal ion in AsqJ. Homolytic cleavage of this moiety during substrate epoxidation generates an activated high-valent ferryl (FeIV = O) species that mediates the next catalytic cycle, possibly without the consumption of the metabolically valuable αKG cosubstrate. Our combined findings provide an important understanding of chemical bond activation principles in complex enzymatic reaction networks and molecular mechanisms of dioxygenases.

Etiological spectrum and antimicrobial resistance of the most frequently isolated pathogens, associated with urinary tract infections in ambulatory patients

Introduction: Urinary tract infections (UTIs) are among the most common infections both in the community and in the hospital setting. Aim: The aim of this study is to investigate the etiological spectrum and antimicrobial resistance of most frequently isolated pathogens, associated with UTIs in ambulatory patients in Varna city, Bulgaria during a seven-month period (October 2020–April 2021). Materials and Methods: A total of 1600 urine samples, collected from patients with suspected UTIs were tested. Screening for bacterial growth was done by HM&L Uroquattro instrument (ALIFAX, Italy). Species identification and antimicrobial susceptibility testing were performed by VITEK 2 Compact System (bioMerieux) and Kirby-Bauer disk diffusion method. Results: E. coli was the most commonly isolated uropathogen regardless of the age group (48%, n = 61), followed by Enterococcus faecalis (33%, n = 42) and other representatives of order Enterobacterales (13.3%, n = 18). The resistance rates in the group of Gram-negative isolates (n = 79) in decreasing order were as follows: ampicillin, 64.5% > trimethoprim/sulfamethoxazole, 36% > ciprofloxacin, 29.1% > amoxicillin-clavulanic acid, 27.8% > cefuroxime, levofloxacin, 21.5% > fosfomycin, 13.1% > ceftriaxone, 12.6% > ceftazidime, 10.1% > gentamicin, nitrofurantoin, 6.5% > nitroxoline, 4.9%. The resistance rates among the isolates of E. faecalis (n = 42) were as follows: ciprofloxacin, 28.6% > gentamicin, 23.8% > levofloxacin, 19% > nitrofurantoin, 4.7% > amoxicillin, 2.4%. No resistance to meropenem, amikacin, vancomycin, and teicoplanin was found in the studied collection of isolates (n = 127). Conclusion: The etiological spectrum of UTIs in ambulatory patients was dominated by E. coli , followed by E. faecalis. In the group of Gram-negative uropathogens, high resistance rates to ampicillin, trimethoprim/sulfamethoxazole and quinolones were detected. Third-generation cephalosporins, fosfomycin, nitrofurantoin and nitroxoline retained very good activity. Among Enterococcus faecalis isolates, the second most commonly isolated bacterial species, a decreased activity of quinolones was found too, but the aminopenicillins and nitrofurantoin remain highly active.

Evaluation of anti-parasitic activities of new quinolones containing nitrofuran moiety against Toxoplasma gondii

Toxoplasmosis is a disease with a worldwide prevalence that is caused by Toxoplasma gondii. Pyrimethamine and sulfadiazine are two pharmacological agents commonly used to treat of this infection. However, they are accompanied by some side effects. Therefore, the identifying of new drugs with low toxocytosis seems to be a matter of vital importance. Quinolones are DNA replication inhibitors, exerting inhibitory effects against many pathogens, including bacteria, mycoplasma, and protozoa. Given the importance of quinolones and their efficacy, the present in vitro study was conducted to investigate the antiparasitic activities of new quinolones (NFQ-2, NFQ-5, and NFQ-6) containing nitrofuran moiety against T. gondii. To this end, Vero cells were incubated with various concentrations of new quinolones and pyrimethamine (positive control) to determine their viability. Subsequently, they were infected with T. gondii (RH strain) and then subjected to drug treatment. The obtained IC50 values were 3.60, 4.84, 5.59, 3.44 and 2.75 μg/mL for NFQ-2, NFQ-5, NFQ-6, ciprofloxacin and pyrimethamine, respectively. The CC50 values for the NFQ-2, NFQ-5, and NFQ-6 were 25.20, 29.89, and 28.43 μg/mL, indicating the selectivity indexes more than 5 for these compounds. The anti-Toxoplasma efficiency was determined by evaluating infection index, number and size of plaques, and T. gondii intracellular proliferation. As the results indicated, the administration of new quinolone derivatives resulted in the reduction of intracellular proliferation, infection index, and the number and size of plaques in comparison to uninfected treated cells (P < 0.05). The results were indicative of a considerable synergetic effect when each of the derivatives was used in combination with pyrimethamine, compared to when used alone. Based on our results, the nitrofuran-derived quinolones can be considered as new leads for the design of new anti-Toxoplasma agents.

Adenine Modification at C7 as a Viable Strategy to Potentiate the Antimalarial Activity of Quinolones.

Although many quinolones have shown promise as potent antimalarials, their clinical development has been slow due to poor performance in vivo. Insights into structural modifications that can improve their therapeutic potential will be very valuable in this vibrant area of research. Our studies involving a library of quinolones which vary in substitution pattern at N1, C3, C6 and C7 positions have shown that the presence of adenine moiety at C7 can bring a noticeable improvement in activity compared to other heterocyclic groups at this location. The most potent compound emerged from this study showed IC50 values of 0.38 μM and 0.75 μM against chloroquine-sensitive and -resistant (W2) strains, respectively. Docking analysis in the Qo site of cytochrome bc1 complex revealed the contribution of a key H-bonding interaction from the adenine unit in target binding. This corroborates with compound-induced loss of mitochondrial functions. These findings not only open avenues for further exploration of antimalarial potential of adenine-modified quinolones, but also suggests broader opportunities during lead-optimization against other antimalarial targets.

Facile N‐Formylation of Amines on Magnetic Fe3O4−CuO Nanocomposites

AbstractA facile, eco‐friendly, efficient, and recyclable heterogeneous catalyst is synthesized by immobilizing copper impregnated on mesoporous magnetic nanoparticles. The surface chemistry analysis of Fe3O4−CuO nanocomposites (NCs) by XRD and XPS demonstrates the synergistic effect between Fe3O4 and CuO nanoparticles, providing mass‐transfer channels for the catalytic reaction. TEM images clearly indicate the impregnation of CuO onto mesoporous Fe3O4. This hydrothermally synthesized eco‐friendly and highly efficient Fe3O4−CuO NCs are applied as a magnetically retrievable heterogeneous catalyst for the N‐formylation of wide range of aliphatic, aromatic, polyaromatic and heteroaromatic amines using formic acid as a formylating agent at room temperature. The catalytic activity of the NCs for N‐formylation is attributable to the synergistic effect between Fe3O4 and CuO nanoparticles. The N‐formylated product is further employed for the synthesis of biologically active quinolone moieties.

In Vitro Antimicrobial Activity of Quinolones Against Major Bacterial Isolates from the Ocular Surface Bacterial Flora of Tertiary Hospital Patients in Japan.

Purpose: To determine the in vitro antimicrobial activity of quinolones against major bacterial isolates from the ocular surface bacterial flora of patients in a tertiary hospital for selection of optimal antibiotic eye drop during the perioperative stage. Methods: The conjunctival sac scraping of 933 patients who underwent ophthalmic surgery was cultivated and bacterial species of the isolates were identified. The minimum inhibitory concentrations (MICs) of gatifloxacin (GFLX), moxifloxacin (MFLX), levofloxacin (LVFX), and tosufloxacin (TFLX) were measured by microdilution methods. The cumulative percentages of MICs of 4 quinolones against major bacteria were calculated. The concentrations of quinolones inhibiting 50% (MIC50) and 90% (MIC90) of the major bacteria were compared. Results: The study mainly included 784 patients scheduled for cataract surgery, 73 for vitrectomy, 30 for corneal transplantation, 30 for conjunctival surgery, 11 for eyelid surgery. The most frequently isolated bacterium was coagulase-negative Staphylococci (CNS) (184 strains), followed by Corynebacterium (107 strains), Staphylococcus aureus (33 strains), Streptococcus (18 strains), and Enterococcus (13 strains). The percentages of methicillin-sensitive CNS isolates for which MIC of GFLX, MFLX, LVFX, and TFLX was 0.06 μg/mL or less were 8.0%, 13.4%, 5.4%, and 63.4%, respectively. Similarly, the percentage for Corynebacterium was 23.0%, 23.0%, 0%, and 35.6%, respectively. MIC50 of TFLX for Streptococcus and Enterococcus showed the lowest values, 0.12 and 0.25 μg/mL, respectively. Conclusions: Among 4 quinolones, TFLX has the highest in vitro antimicrobial activity against major bacterial isolates from the ocular surface bacterial flora of patients in a tertiary hospital.

Fluoroquinolone antibiotics: An overview

Fluoroquinolones are the type of antibacterial agents more extensively used from the past few years and will be continued to be used even in the next decade. The fluoroquinolones show their action by inhibiting the DNA gyrase and topoisomerase enzymes. The main mechanism fluoroquinolones is mutations that alter the accumulation of fluoroquinolones in bacteria. The broad use of the fluoroquinolones is discussed. They are useful in the treatment of urinary tract infections, prostatitis, sexually transmitted diseases, gastrointestinal infections, osteomyelitis, and respiratory tract infections. Their structure–activity relationship is also discussed and that is helpful in ongoing new researches on quinolones that may enhance the antibacterial activity of quinolones.

Inhibition of indole production increases the activity of quinolone antibiotics against E. coli persisters

Persisters are a sub-population of genetically sensitive bacteria that survive antibiotic treatment by entering a dormant state. The emergence of persisters from dormancy after antibiotic withdrawal leads to recurrent infection. Indole is an aromatic molecule with diverse signalling roles, including a role in persister formation. Here we demonstrate that indole stimulates the formation of Escherichia coli persisters against quinolone antibiotics which target the GyrA subunit of DNA gyrase. However, indole has no effect on the formation of E. coli persisters against an aminocoumarin, novobiocin, which targets the GyrB subunit of DNA gyrase. Two modes of indole signalling have been described: persistent and pulse. The latter refers to the brief but intense elevation of intracellular indole during stationary phase entry. We show that the stimulation of quinolone persisters is due to indole pulse, rather than persistent, signalling. In silico docking of indole on DNA gyrase predicts that indole docks perfectly to the ATP binding site of the GyrB subunit. We propose that the inhibition of indole production offers a potential route to enhance the activity of quinolones against E. coli persisters.

Potential Ototopical Antiseptics for the Treatment of Active Chronic Otitis Media: An In Vitro Evaluation.

Primary: to compare, in vitro, the antimicrobial activity of different antiseptic agents versus quinolone drops, against the common organisms of chronic otitis media.Secondary: to examine the possible role of pH on the antimicrobial activity of the antiseptic solutions. Three antiseptic powders (boric acid; iodine; and a 1:1 combination of these two) and four solutions (2% boric acid; 2% acetic acid; 3.25% aluminum acetate; and 5% povidone iodine) were tested against five bacteria and two fungi common in chronic otitis media, using both agar plates and the modified broth dilution method. These results were compared with the antimicrobial activity of quinolone drops.The potential role of pH of solutions was tested by reducing the acidity of the agents and repeating the broth dilution. Of the powders, iodine, and iodine/boric acid combined, are very effective against all organisms. Boric acid powder showed moderate effectiveness against all organisms. All solutions performed poorly on the agar plates. 5% povidone iodine has good effectivity when tested with the broth dilution method. 3.25% aluminum acetate had the best activity against Pseudomonas aeruginosa. Boric acid powder and 5% povidone iodine solution show promise for clinical use. Boric acid powder has proven clinical effectiveness. 5% povidone iodine requires further clinical research. Although very effective in vitro, iodine powder is toxic to tissues and cannot be recommended for clinical use. The pH of solutions does not seem to play a significant role in their antimicrobial activity in vitro.

Identification and quantification of antimicrobial activity in commercially available chicken meat in a large urban centre in Pakistan

BackgroundLarge-scale use and misuse of antibacterial agents for infection prevention and growth promotion in chicken has grown alongside mass production of poultry as a primary protein source in human diet. This has led to concern about promotion of antibiotic resistance among bacteria of clinical significance to human disease. The objectives of this study are to identify which, if any, antimicrobials are commonly found in commercially available broiler chicken and determining the minimum amount of meat with enough microbial inhibitory activity that can be measured in routine culture. Four test organisms, namely ATCC 25922, ATCC 51299, clinical isolate MRSA and clinical isolate E. coli were used. The antimicrobial sensitivity profiles of the test organisms were determined against beta-lactams, tetracyclines, aminoglycosides, sulphonamides, fluoroquinolones and phenicols. 8 mm tissue pieces of liver, muscle and kidney samples were obtained and plated on all four plates of our test organisms. The zones of inhibition, if any, around the tissue samples determined the presence of antimicrobial residues in meat. 270 tissue samples of liver, muscle and kidney were tested for the presence of antimicrobial residues. In total 90 freshly butchered broiler chicken samples were collected, each contributing a liver, kidney and a muscle tissue sample. The samples were collected randomly from butcher shops across geographical bins of the city of Lahore.The results showed that 73.3% of the samples were positive for antimicrobial activity. Of these 69.6% of the samples were positive for the presence of sulfonamides, 9.3% had flurphenicol, 7.0% had quinolone activity, 6.7% had aminoglycoside activity and 3.7% had tetracyclines in them.

Topological index Nclass as a factor determining the antibacterial activity of quinolones against Escherichia coli.

Aim: Due to antibiotic resistance and the lack of investment in antimicrobial R&D, quantitative structure-activity relationship (SAR) methods appear as an ideal approach for the discovery of new antibiotics. Result & methodology: Molecular topology and linear discriminant analysis were used to construct a model to predict activity against Escherichia coli. This model establishes new SARs, of which, molecular size and complexity (Nclass), stand out for their discriminant power. This model was used for the virtual screening of the Index Merck database, with results showing a high success rate as well as a moderate restriction. Conclusion: The model efficiently finds new active compounds. The topological index Nclass can act as a filter in other quantitative structure-activity relationship models predicting activity against E. coli.

Quinolone derivatives: Potential anti-HIV agent-development and application.

Acquired immune deficiency syndrome (AIDS)/human immunodeficiency virus (HIV) is one of the largest and most devastating public health pandemics throughout the world. The global pandemic of drug-sensitive HIV and the increasing threat from drug-resistant HIV result in an urgent need to develop more effective anti-HIV candidates. Quinolone represents a significant class of privileged heterocycles, and its derivatives possess promising in vitro and in vivo anti-HIV properties. The 4-quinolone elvitegravir has already been approved for the treatment of HIV; thus, quinolone derivatives might be promising candidates with anti-HIV activity. This review emphasizes quinolone derivatives with potential anti-HIV activity, covering articles published between 1992 and 2019. The structure-activity relationship is also discussed to provide insights for further development of more active quinolone derivatives.

Towards anticancer fluoroquinolones: A review article.

Different studies about the anticancer potential of several medically used antibacterial fluoroquinolones have been established. Fluoroquinolone derivatives, like some anti-cancer drugs, such as doxorubicin, can achieve antitumor activity via poisoning of type II human DNA topoisomerases. Interestingly, structural features required for the anticancer activity of quinolones have been determined. Most of the chemical modifications required to convert antibacterially acting fluoroquinolones into their anticancer analogs were at position 7 and the carboxylic group at position 3. This review highlights the antitumor potential of fluoroquinolones in general and summarizes the chemical modifications carried out on fluoroquinolones to become anticancer agents. Moreover, the review gives a quick recap on metal ion chelates with fluoroquinolones and their substantial role in topoisomerase poisoning and antitumor potential improvement. Hence, it should be highly interesting for researchers attempting to design and synthesize novel anticancer fluoroquinolone candidates.

Ferulic acid potentiates the antibacterial activity of quinolone-based antibiotics against Acinetobacter baumannii

Ferulic acid is a cinnamic derivative of phenolic acid and its pharmacophore (catechol) is responsible for antioxidant, prooxidant and antibacterial activities. In this study, we evaluated the influence of ferulic acid on the antibacterial activity of quinolone-based antibiotics against Acinetobacter baumannii. The minimum inhibitory concentration of ferulic acid against Acinetobacter baumannii AB5075 were considerably lowered for ΔsodB and ΔkatG mutants. Checkerboard assay shows synergistic interactions between ferulic acid and quinolones. In a murine sepsis model, ferulic acid potentiated the antibacterial activities of quinolones. Ferulic acid amplified quinolones-induced redox imbalance by increasing superoxide ion generation, NAD+/NADH ratio and ADP/ATP ratio. Conversely, the level of reduced glutathione was significantly lowered. We conclude that ferulic acid potentiates the antibacterial activity of quinolone-based antibiotics against A. baumannii by increasing ROS generation, energy metabolism and electron transport chain activity with a concomitant decrease in glutathione.

Our Evolving Understanding of the Mechanism of Quinolones.

The maintenance of DNA supercoiling is essential for the proper regulation of a plethora of biological processes. As a consequence of this mode of regulation, ahead of the replication fork, DNA replication machinery is prone to introducing supercoiled regions into the DNA double helix. Resolution of DNA supercoiling is essential to maintain DNA replication rates that are amenable to life. This resolution is handled by evolutionarily conserved enzymes known as topoisomerases. The activity of topoisomerases is essential, and therefore constitutes a prime candidate for targeting by antibiotics. In this review, we present hallmark investigations describing the mode of action of quinolones, one of the antibacterial classes targeting the function of topoisomerases in bacteria. By chronologically analyzing data gathered on the mode of action of this imperative antibiotic class, we highlight the necessity to look beyond primary drug-target interactions towards thoroughly understanding the mechanism of quinolones at the level of the cell.