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ACS Bio & Med Chem Au Dec 2023Fluoroquinolones are an important class of antibiotics with broad-spectrum antibacterial and antitubercular activity. Here, we describe the design and synthesis of a...
Fluoroquinolones are an important class of antibiotics with broad-spectrum antibacterial and antitubercular activity. Here, we describe the design and synthesis of a series of 38 4-substituted piperazinyl norfloxacin derivatives. Their activity and mechanism of action were characterized using , , and approaches. Several compounds displayed interesting activities against both Gram-negative and Gram-positive bacteria, and few displayed antimycobacterial activity, whereby some were as potent as norfloxacin and ciprofloxacin. Molecular docking experiments suggested that the new derivatives inhibit both DNA gyrase and DNA topoisomerase IV in a similar manner as norfloxacin. Selecting the most promising candidates for experimental mode of action analysis, we confirmed DNA gyrase and topoisomerase IV as targets of all tested compounds using enzymatic assays. Phenotypic analysis of both and confirmed a typical gyrase inhibition phenotype for all of the tested compounds. Assessment of possible additional targets revealed three compounds with unique effects on the cell wall synthesis machinery, suggesting that they may have an additional target in this pathway. Comparison with known cell wall synthesis inhibitors showed that the new compounds elicit a distinct and, so far, unique phenotype, suggesting that they act differently from known cell wall synthesis inhibitors. Interestingly, our phenotypic analysis revealed that both norfloxacin and ciprofloxacin displayed additional cellular effects as well, which may be indicative of the so far unknown additional mechanisms of fluoroquinolones.
PubMed: 38144255
DOI: 10.1021/acsbiomedchemau.3c00038 -
ACS Omega Dec 2023L. (Cistaceae) is a medicinal plant with several folkloric applications, including being used for urinary tract infections and as a food additive. In this study, the...
L. (Cistaceae) is a medicinal plant with several folkloric applications, including being used for urinary tract infections and as a food additive. In this study, the polyphenolic diversity and the antioxidant, antidiabetic, and antimicrobial activities of the methanolic extract were evaluated. Spectrophotometric and HPLC-based analyses using standard polyphenolic compounds were conducted to measure the phenolics and flavonoids in the plant extract. The in vitro DPPH, ORAC, FRAP, and α-glucosidase assays were used to evaluate the plant's antioxidant and antidiabetic activities. Furthermore, disc diffusion and MIC-based microdilution tests were applied to evaluate the antimicrobial activity of the plant against broad-spectrum microorganisms. The analysis revealed the existence of high phenolic and flavonoid quantities that were measured at 302.59 ± 0.6 μg GAE and 134.3 ± 0.5 μg RE, respectively. The HPLC-based analysis revealed the existence of 18 phenolic acids and 8 flavonoids. The major phenolic acid was ellagic acid (169.03 ppm), while catechin was the major flavonoid (91.80 ppm). Remarkable antioxidant activity was measured using three different assays: DPPH, ORAC, and FRAP. Furthermore, strong inhibition of α-glucosidase compared to acarbose was recorded for the plant extract (IC 0.924 ± 0.6). The results showed that 's extract had a strong anti- effect with MIC value of 0.98 μg\mL and IZD value of 32.2 ± 0.58 mm compared to 25.3 ± 0.18 mm for gentamycin, the positive control. Moreover, , , , , and all showed significant growth inhibition in response to the extract, a result that may be related to the use of the plant in traditional medicine to treat urinary tract infections. The docking study indicated the higher binding affinity of the major identified compounds, i.e., ellagic acid, rutin, naringin, catechin, and punicalagin, to the gyrase-DNA complex, which might suggest the possible mechanisms of the plant as antimicrobial agents.
PubMed: 38144113
DOI: 10.1021/acsomega.3c07545 -
Molecules (Basel, Switzerland) Dec 2023Urinary tract infection is an infectious disease that requires immediate treatment. It can occur in any age group and involves both genders equally. The present study...
Urinary tract infection is an infectious disease that requires immediate treatment. It can occur in any age group and involves both genders equally. The present study was to check the resistance of some antibiotics and to assess the antibacterial potential of three extracts of three plants against notorious bacteria involved in urinary tract infections. Along with assessing the antibacterial activity of plant extracts, we checked for the anticancer potential of these extracts against the cancer cell lines MCF-7 and A2780. Cancer is the leading cause of mortality in developed countries. Determinations of total flavonoid content, total phenolic content, total alkaloid content, total tannin content, total carotenoid content, and total steroid content were performed. The disk diffusion method was used to analyze the antibacterial activity of plant extracts. Ethanolic extract of showed sensitivity (25-28 mm) against bacteria, whereas chloroform and hexane extracts showed resistance against all bacteria except (25 mm). Ethanolic extract of L. showed sensitivity (22-25 mm) against bacteria, whereas chloroform and hexane extracts showed resistance. Ethanolic extract of L. showed sensitivity (8-16 mm) against all bacteria except , whereas chloroform and hexane extracts showed resistance. Positive controls showed variable zones of inhibition (2-60 mm), and negative control showed 0-1 mm. The antibiotic resistance was much more prominent in the case of hexane and chloroform extracts of all plants, whereas ethanolic extract showed a sensitivity of bacteria against extracts. Both cell lines, MCF-7 and A2780, displayed decreased live cells when treated with plant extracts.
Topics: Male; Female; Humans; Pistacia; Olea; Hexanes; Cell Line, Tumor; MCF-7 Cells; Chloroform; Ovarian Neoplasms; Anti-Bacterial Agents; Plant Extracts; Staphylococcus; Bacteria; Microbial Sensitivity Tests
PubMed: 38138636
DOI: 10.3390/molecules28248148 -
Molecules (Basel, Switzerland) Dec 2023The emergence of antimicrobial resistance due to the widespread and inappropriate use of antibiotics has now become the global health challenge. Flavonoids have long...
The emergence of antimicrobial resistance due to the widespread and inappropriate use of antibiotics has now become the global health challenge. Flavonoids have long been reported to be a potent antimicrobial agent against a wide range of pathogenic microorganisms in vitro. Therefore, new antibiotics development based on flavonoid structures could be a potential strategy to fight against antibiotic-resistant infections. This research aims to screen the potency of flavonoids of the genus Erythrina as an inhibitor of bacterial ATPase DNA gyrase B. From the 378 flavonoids being screened, 49 flavonoids show potential as an inhibitor of ATPase DNA gyrase B due to their lower binding affinity compared to the inhibitor and ATP. Further screening for their toxicity, we identified 6 flavonoids from these 49 flavonoids, which are predicted to have low toxicity. Among these flavonoids, erystagallin B () is predicted to have the best pharmacokinetic properties, and therefore, could be further developed as new antibacterial agent.
Topics: Anti-Bacterial Agents; DNA Gyrase; Flavonoids; Erythrina; Adenosine Triphosphatases; Microbial Sensitivity Tests; Bacteria; Topoisomerase II Inhibitors
PubMed: 38138500
DOI: 10.3390/molecules28248010 -
Frontiers in Pharmacology 2023Antimicrobial resistance in the sexually transmitted bacterium is compromising the management and control of gonorrhea globally. Optimized use and enhanced stewardship...
Antimicrobial resistance in the sexually transmitted bacterium is compromising the management and control of gonorrhea globally. Optimized use and enhanced stewardship of current antimicrobials and development of novel antimicrobials are imperative. The first in class zoliflodacin (spiropyrimidinetrione, DNA Gyrase B inhibitor) is a promising novel antimicrobial in late-stage clinical development for gonorrhea treatment, i.e., the phase III randomized controlled clinical trial (ClinicalTrials.gov Identifier: NCT03959527) was recently finalized, and zoliflodacin showed non-inferiority compared to the recommended ceftriaxone plus azithromycin dual therapy. Doxycycline, the first-line treatment for chlamydia and empiric treatment for non-gonococcal urethritis, will be frequently given together with zoliflodacin because gonorrhea and chlamydia coinfections are common. In a previous static study, it was indicated that doxycycline/tetracycline inhibited the gonococcal killing of zoliflodacin in 6-h time-kill curve analysis. In this study, our dynamic hollow-fiber infection model (HFIM) was used to investigate combination therapies with zoliflodacin and doxycycline. Dose-range experiments using the three gonococcal strains WHO F (susceptible to relevant therapeutic antimicrobials), WHO X (extensively drug-resistant, including ceftriaxone-resistant; zoliflodacin-susceptible), and SE600/18 (zoliflodacin-susceptible strain with GyrB S467N substitution) were conducted simulating combination therapy with a single oral dose of zoliflodacin 0.5-4 g combined with a doxycycline daily oral dose of 200 mg administered as 100 mg twice a day, for 7 days (standard dose for chlamydia treatment). Comparing combination therapy of zoliflodacin (0.5-4 g single dose) plus doxycycline (200 mg divided into 100 mg twice a day orally, for 7 days) to zoliflodacin monotherapy (0.5-4 g single dose) showed that combination therapy was slightly more effective than monotherapy in the killing of and suppressing emergence of zoliflodacin resistance. Accordingly, WHO F was eradicated by only 0.5 g single dose of zoliflodacin in combination with doxycycline, and WHO X and SE600/18 were both eradicated by a 2 g single dose of zoliflodacin in combination with doxycycline; no zoliflodacin-resistant populations occurred during the 7-day experiment when using this zoliflodacin dose. When using suboptimal (0.5-1 g) zoliflodacin doses together with doxycycline, gonococcal mutants with increased zoliflodacin MICs, due to GyrB D429N and the novel GyrB T472P, emerged, but both the mutants had an impaired biofitness. The present study shows the high efficacy of zoliflodacin plus doxycycline combination therapy using a dynamic HFIM that more accurately and comprehensively simulate gonococcal infection and their treatment, i.e., compared to static models, such as short-time checkerboard experiments or time-kill curve analysis. Based on our dynamic HFIM work, zoliflodacin plus doxycycline for the treatment of both gonorrhea and chlamydia can be an effective combination.
PubMed: 38130409
DOI: 10.3389/fphar.2023.1291885 -
Nanoscale Advances Dec 2023We have employed a co-precipitation method to synthesize different concentrations of carbon spheres (CSs) doped with cadmium sulfide (CdS) quantum dots (QDs) for...
We have employed a co-precipitation method to synthesize different concentrations of carbon spheres (CSs) doped with cadmium sulfide (CdS) quantum dots (QDs) for catalytic reduction and antibacterial applications. Various morphological and structural characterization techniques were used to comprehensively analyze the CS effect on CdS QDs. The catalytic reduction efficiency of CS-doped CdS QDs was evaluated using rhodamine B dye. The antibacterial efficacy was also assessed against the pathogenic microorganism (), and substantial destruction in the inhibitory zone was measured. Finally, the synthesized CS-doped CdS QDs demonstrated favorable results for catalytic reduction and antibacterial applications. Computational studies verified the suppressive impact of these formed QDs on DNA gyrase and β-lactamase of
PubMed: 38125601
DOI: 10.1039/d3na00579h -
Nucleic Acids Research Feb 2024Mycobacterium tuberculosis, the causative agent of tuberculosis, is a growing threat to global health, with recent efforts towards its eradication being reversed in the...
Mycobacterium tuberculosis, the causative agent of tuberculosis, is a growing threat to global health, with recent efforts towards its eradication being reversed in the wake of the COVID-19 pandemic. Increasing resistance to gyrase-targeting second-line fluoroquinolone antibiotics indicates the necessity to develop both novel therapeutics and our understanding of M. tuberculosis growth during infection. ParDE toxin-antitoxin systems also target gyrase and are regulated in response to both host-associated and drug-induced stress during infection. Here, we present microbiological, biochemical, structural, and biophysical analyses exploring the ParDE1 and ParDE2 systems of M. tuberculosis H37Rv. The structures reveal conserved modes of toxin-antitoxin recognition, with complex-specific interactions. ParDE1 forms a novel heterohexameric ParDE complex, supported by antitoxin chains taking on two distinct folds. Curiously, ParDE1 exists in solution as a dynamic equilibrium between heterotetrameric and heterohexameric complexes. Conditional remodelling into higher order complexes can be thermally driven in vitro. Remodelling induces toxin release, tracked through concomitant inhibition and poisoning of gyrase activity. Our work aids our understanding of gyrase inhibition, allowing wider exploration of toxin-antitoxin systems as inspiration for potential therapeutic agents.
Topics: Humans; Antitoxins; Bacterial Proteins; DNA Gyrase; Fluoroquinolones; Mycobacterium tuberculosis; Pandemics; Tuberculosis; Bacterial Toxins
PubMed: 38113275
DOI: 10.1093/nar/gkad1220 -
The Journal of Antimicrobial... Feb 2024
Topics: Humans; Anti-Bacterial Agents; Australia; Drug Resistance, Bacterial; Fluoroquinolones; Macrolides; Mutation; Mycoplasma genitalium; Mycoplasma Infections; Queensland; DNA Gyrase; Bacterial Proteins
PubMed: 38102067
DOI: 10.1093/jac/dkad373 -
Microbial Genomics Dec 2023In this study, we characterized 54 clinical isolates of collected in North Lebanon between 2009 and 2017 through phenotypic and genomic analyses. The most prevalent...
In this study, we characterized 54 clinical isolates of collected in North Lebanon between 2009 and 2017 through phenotypic and genomic analyses. The most prevalent serogroup was accounting for 46.3 % (25/54) of the isolates, followed by (27.8 %, 15/54), (18.5 %, 10/54) and (7.4 %, 4/54). Only three isolates were pan-susceptible, and 87 % (47/54) of the isolates had multidrug resistance phenotypes. Notably, 27.8 % (15/54) of the isolates were resistant to third-generation cephalosporins (3GCs) and 77.8 % (42/54) were resistant to nalidixic acid. 3GC resistance was mediated by the extended-spectrum beta-lactamase genes and , which were present on various plasmids. Quinolone resistance was conferred by single point mutations in the DNA gyrase gene, leading to GyrA S83L, GyrA D87Y or GyrA S83A amino acid substitutions. This is the first study, to our knowledge, to provide genomic insights into the serotypes of circulating in Lebanon and the various antimicrobial resistance determinants carried by these strains.
Topics: Anti-Bacterial Agents; Lebanon; Drug Resistance, Bacterial; Genomics; Point Mutation
PubMed: 38100171
DOI: 10.1099/mgen.0.001157 -
RSC Medicinal Chemistry Dec 2023Fluoroquinolones are broad-spectrum antibiotics that target gyrase and topoisomerase IV, involved in DNA compaction and segregation. We synthesized 28 novel norfloxacin...
Fluoroquinolones are broad-spectrum antibiotics that target gyrase and topoisomerase IV, involved in DNA compaction and segregation. We synthesized 28 novel norfloxacin hydroxamic acid derivatives with additional metal-chelating and hydrophobic pharmacophores, designed to enable interactions with additional drug targets. Several compounds showed equal or better activity than norfloxacin against Gram-positive, Gram-negative, and mycobacteria, with MICs as low as 0.18 μM. The most interesting derivatives were selected for , , and mode of action studies. Molecular docking, enzyme inhibition, and bacterial cytological profiling confirmed inhibition of gyrase and topoisomerase IV for all except two tested derivatives (10f and 11f). Further phenotypic analysis revealed polypharmacological effects on peptidoglycan synthesis for four derivatives (16a, 17a, 17b, 20b). Interestingly, compounds 17a, 17b, and 20b, showed never seen before effects on cell wall synthetic enzymes, including MreB, MurG, and PonA, suggesting a novel mechanism of action, possibly impairing the lipid II cycle.
PubMed: 38099058
DOI: 10.1039/d3md00309d