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International Journal of Molecular... Feb 2024Fluoroquinolones are potentially active against . Rapidly increased minimum inhibitory concentrations (MICs) and emerging point mutations in the quinolone...
Fluoroquinolones are potentially active against . Rapidly increased minimum inhibitory concentrations (MICs) and emerging point mutations in the quinolone resistance-determining regions (QRDRs) following exposure to fluoroquinolones have been reported in . We aimed to investigate point mutations in QRDRs through exposure to levofloxacin (1 × MIC) combinations with different concentrations (0.5× and 1 × MIC) of minocycline, rifampin, cefoperazone/sulbactam, or sulfamethoxazole/trimethoprim in comparison with exposure to levofloxacin alone. Of the four isolates that were clinically collected, lower MICs of levofloxacin were disclosed in cycle 2 and 3 of induction and selection in all levofloxacin combination groups other than levofloxacin alone (all = 0.04). Overall, no mutations were discovered in and throughout the multicycles inducted by levofloxacin and all its combinations. Regarding the vastly increased MICs, the second point mutations in and/or in one isolate (strain no. 1) occurred in cycle 2 following exposure to levofloxacin plus 0.5 × MIC minocycline, but they were delayed appearing in cycle 5 following exposure to levofloxacin plus 1 × MIC minocycline. Similarly, the second point mutation in and/or occurred in another isolate (strain no. 3) in cycle 4 following exposure to levofloxacin plus 0.5 × MIC sulfamethoxazole/trimethoprim, but no mutation following exposure to levofloxacin plus 1 × MIC sulfamethoxazole/trimethoprim was disclosed. In conclusion, the rapid selection of mutants with high MICs after levofloxacin exposure could be effectively delayed or postponed by antimicrobial combination with other in vitro active antibiotics.
Topics: Levofloxacin; Minocycline; DNA Gyrase; Anti-Bacterial Agents; Fluoroquinolones; Microbial Sensitivity Tests; Mutation; Sulfamethoxazole; Trimethoprim; Drug Resistance, Bacterial; Flavobacteriaceae
PubMed: 38396892
DOI: 10.3390/ijms25042215 -
The Journal of Antimicrobial... Apr 2024Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is increasing worldwide, with Mycobacterium avium complex (MAC) and Mycobacterium abscessus as the predominant...
BACKGROUND
Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is increasing worldwide, with Mycobacterium avium complex (MAC) and Mycobacterium abscessus as the predominant pathogens. Current treatments are poorly tolerated and modestly effective, highlighting the need for new treatments. SPR719, the active moiety of the benzimidazole prodrug SPR720, inhibits the ATPase subunits of DNA gyrase B, a target not exploited by current antibiotics, and therefore, no cross-resistance is expected with standard-of-care (SOC) agents.
OBJECTIVES
To evaluate the in vitro activity of SPR719 against MAC and M. abscessus clinical isolates, including those resistant to SOC agents, and in vivo efficacy of SPR720 in murine non-tuberculous mycobacteria (NTM) pulmonary infection models.
METHODS
NTM isolates were tested for susceptibility to SPR719. Chronic C3HeB/FeJ and severe combined immunodeficient murine models of pulmonary infection were used to assess efficacy of SPR720 against MAC and M. abscessus, respectively.
RESULTS
SPR719 was active against MAC (MIC90, 2 mg/L) and M. abscessus (MIC90, 4 mg/L) clinical isolates. Efficacy of SPR720 was demonstrated against MAC pulmonary infection, both as a monotherapy and in combination with SOC agents. SPR720 monotherapy exhibited dose-dependent reduction in bacterial burden, with the largest reduction observed when combined with clarithromycin and ethambutol. Efficacy of SPR720 was also demonstrated against M. abscessus pulmonary infection where monotherapy exhibited a dose-dependent reduction in bacterial burden with further reductions detected when combined with SOC agents.
CONCLUSIONS
In vitro activity of SPR720 against common NTM pathogens and efficacy in murine infections warrant the continued clinical evaluation of SPR720 as a new oral option for the treatment of NTM-PD.
Topics: Humans; Animals; Mice; Nontuberculous Mycobacteria; Mycobacterium Infections, Nontuberculous; Disease Models, Animal; Mycobacterium avium Complex; Anti-Bacterial Agents; Lung Diseases; Pneumonia
PubMed: 38394463
DOI: 10.1093/jac/dkae046 -
Biology Jan 2024DNA gyrase is essential for the successful replication of circular chromosomes, such as those found in most bacterial species, by relieving topological stressors... (Review)
Review
DNA gyrase is essential for the successful replication of circular chromosomes, such as those found in most bacterial species, by relieving topological stressors associated with unwinding the double-stranded genetic material. This critical central role makes gyrase a valued target for antibacterial approaches, as exemplified by the highly successful fluoroquinolone class of antibiotics. It is reasonable that the activity of gyrase could be intrinsically regulated within cells, thereby helping to coordinate DNA replication with doubling times. Numerous proteins have been identified to exert inhibitory effects on DNA gyrase, although at lower doses, it can appear readily reversible and therefore may have regulatory value. Some of these, such as the small protein toxins found in plasmid-borne addiction modules, can promote cell death by inducing damage to DNA, resulting in an analogous outcome as quinolone antibiotics. Others, however, appear to transiently impact gyrase in a readily reversible and non-damaging mechanism, such as the plasmid-derived Qnr family of DNA-mimetic proteins. The current review examines the origins and known activities of protein inhibitors of gyrase and highlights opportunities to further exert control over bacterial growth by targeting this validated antibacterial target with novel molecular mechanisms. Furthermore, we are gaining new insights into fundamental regulatory strategies of gyrase that may prove important for understanding diverse growth strategies among different bacteria.
PubMed: 38392303
DOI: 10.3390/biology13020084 -
Journal of Advanced Pharmaceutical... 2024Luteolin exhibited antibacterial activity against and its chemical structure similar to that of ciprofloxacin (CPF) which works by inhibiting DNA gyrase. Filtrate from...
Luteolin exhibited antibacterial activity against and its chemical structure similar to that of ciprofloxacin (CPF) which works by inhibiting DNA gyrase. Filtrate from passion fruit extract containing luteolin and its derivatives could inhibit extended-spectrum β-lactamase (ESBL)-producing . . Antibacterial compounds that can also inhibit ESBL will be valuable compounds to overcome the problem of resistant bacteria. This study aimed to ensure the potency of luteolin and luteolin derivatives targeting DNA gyrase and ESBL by approach. Docking simulation of ligands L1-L14 was performed using AutoDock Vina, and pharmacokinetics and toxicity (absorption, distribution, metabolism, excretion, and toxicity) profiles were predicted by pKCSM online. The docking result revealed higher binding affinity on DNA gyrase (PDB.1KZN) of 12 luteolin derivatives (energy <-7.6 kcal/mol) compared to CPF and higher affinity (energy <-6.27 kcal/mol) of all compounds than clavulanic acid against ESBL CTX-M-15 (PDB.4HBU). The compounds could be absorbed through the human intestine moderately, which showed low permeability to blood-brain barrier, nontoxic and nonhepatotoxic. The most active luteolin glycoside (L6) is capable to inhibit DNA gyrase and ESBL from which provided the potential against resistant bacteria and was promoted as lead compounds to be developed further.
PubMed: 38389968
DOI: 10.4103/JAPTR.JAPTR_217_23 -
Zhonghua Yu Fang Yi Xue Za Zhi [Chinese... Feb 2024By conducting retrospective analysis, this study aim to investigate the resistance mechanism of quinolones in non-typhoidal Salmonella (NTS). A total of 105 strains of...
By conducting retrospective analysis, this study aim to investigate the resistance mechanism of quinolones in non-typhoidal Salmonella (NTS). A total of 105 strains of NTS isolated from clinical specimens from the Fifth Affiliated Hospital of Southern Medical University from May 2020 to February 2021 were used as research objects. VITEK2 Compact automatic identification drug sensitivity analysis system and serological test were used to identify the strains. The sensitivity of the strains to ciprofloxacin, levofloxacin and nalidixic acid was detected by AGAR dilution method. The whole genome of 105 strains of NTS was sequenced. Abricate and other softwares were used to analyze drug-resistant genes, including plasmid-mediated quinolone resistance gene (PMQR) and Quinolone resistance determination region (QRDR). Serotypes and ST types were analyzed using SISTR and MLST, and phylogenetic trees were constructed. The results showed that the NTS isolated in this region were mainly ST34 (53.3%). The drug sensitivity results showed that the drug resistance rates of NTS to ciprofloxacin, levofloxacin and nalidixic acid were 30.4%, 1.9% and 22.0%, respectively, and the intermediate rates of ciprofloxacin and levofloxacin were 27.6% and 54.2%.A total of 46 (74.2%) of the 62 quinolone non-susceptible strains carried the PMQR gene, mainly (80.4%), followed by (15.2%); there were 14 NTS and 8 NTS had and gene mutations, respectively. The was mutations at the amino acid position 87, Asp87Tyr, Asp87Asn, Asp87Gly, and Thr57Ser mutations were detected in . In conclusion, this study found that NTS had relatively high resistance to quinolones, carrying gene mainly resulted in decreased sensitivity of NTS to ciprofloxacin and levofloxacin, and :87 mutation mainly resulted in NTS resistance to Nalidixic acid; in clinical isolates showed clonal transmission and required further epidemiological surveillance.
Topics: Humans; Quinolones; Nalidixic Acid; Levofloxacin; Phylogeny; Multilocus Sequence Typing; Retrospective Studies; DNA Gyrase; Salmonella; Ciprofloxacin; Plasmids; Mutation; Microbial Sensitivity Tests; Anti-Bacterial Agents; Drug Resistance, Bacterial
PubMed: 38387958
DOI: 10.3760/cma.j.cn112150-20230729-00039 -
Future Medicinal Chemistry Mar 2024Antimicrobial resistance has become a critical health concern, and quorum-sensing exacerbates the resistance by facilitating cell-to-cell communication within the...
Antimicrobial resistance has become a critical health concern, and quorum-sensing exacerbates the resistance by facilitating cell-to-cell communication within the microbial community, leading to severe pathogenic outbreaks. Novel 1-(2-((5-[1,2,4]-triazino[5,6-]indol-3-yl)thio)acetyl)indoline-2,3-diones were synthesized. The title compounds exhibit outstanding anti-quorum-sensing efficacy, and compound demonstrated the maximum proficiency (IC = 0.0504 μg/ml). The hybrids displayed potent antioxidant action, and compound showed the highest antioxidant ability (IC = 40.71 μg/ml). Molecular docking of the isatin hybrids against DNA gyrase and quorum-sensing receptor CviR validated the observed findings. The befitting pharmacokinetic profile of the synthesized drug candidates was ascertained through absorption, distribution, metabolism, excretion and toxicity screening. The remarkable biocompetence of the synthesized triazinoindoles may help to combat drug-resistant infections.
Topics: Molecular Docking Simulation; Anti-Bacterial Agents; Microbial Sensitivity Tests; Antioxidants; Quorum Sensing; Anti-Infective Agents; Biofilms
PubMed: 38375563
DOI: 10.4155/fmc-2023-0313 -
Molecular Diversity Feb 2024Infections from multidrug-resistant (MDR) bacteria have emerged as a paramount global health concern, and the therapeutic effectiveness of current treatments is swiftly...
Infections from multidrug-resistant (MDR) bacteria have emerged as a paramount global health concern, and the therapeutic effectiveness of current treatments is swiftly diminishing. An urgent need exists to explore innovative strategies for countering drug-resistant bacteria. Bacterial DNA gyrase, functioning as an ATP-dependent enzyme, plays a pivotal role in the intricate processes of transcription, replication, and chromosome segregation within bacterial DNA. This renders it a prime target for the development of innovative antibacterial agents. However, the experimental identification of bacterial DNA gyrase inhibitors faces multifaceted challenges due to current methodological constraints. Recognizing its significance, this study developed 56 computational models designed for predicting bacterial DNA gyrase inhibitors. These models employed seven distinct molecular fingerprints and eight machine learning algorithms. Among these models, Model_2D, created using KlekotaRoth fingerprints and the SVM algorithm, stands out as the most robust performer (ACC = 0.86, MCC = 0.63, G-mean = 0.82). Moreover, given the limited exploration of structural fragments required for DNA Gyrase B inhibitors, crucial structural fingerprints influencing DNA Gyrase B inhibitors were identified through Bayesian classification. Subsequently, we conducted molecular docking to reveal the binding modes between these crucial structural fingerprints and the active site of DNA gyrase B. In conclusion, the present study aimed to develop the optimal classification model for bacterial DNA gyrase inhibitors, offering invaluable support to medicinal chemists creating innovative DNA gyrase inhibitors.
PubMed: 38372837
DOI: 10.1007/s11030-024-10806-y -
Drug Development Research Apr 2024Four piroxicam metal complexes; NiL , PtL , PdL , and AgL were synthesized and characterized by different techniques with enhanced antibacterial and anticancer activity....
Synthesis, characterization, molecular modeling studies, and biological evaluation of metal piroxicam complexes (M = Ni(II), Pt(IV), Pd(II), Ag(I)) as antibacterial and anticancer agents.
Four piroxicam metal complexes; NiL , PtL , PdL , and AgL were synthesized and characterized by different techniques with enhanced antibacterial and anticancer activity. Regarding in vitro antimicrobial activity, complex NiL displayed potent antibacterial effect against Escherichia coli and Pseudomonas aeruginosa that was 1.9-folds higher than piroxicam (minimum inhibitory concentration [MIC] = 31.85, 65.32 µM), respectively. In case of G+ve bacteria, complex PtL had potent activity on Staphylococcus aureus which was 2.1-folds higher than piroxicam (MIC = 43.12 µM), while activity of complex AgL against Enterococcus faecalis was threefolds higher than piroxicam (MIC = 74.57 µM. Complexes PtL and PdL exhibited higher inhibition of DNA gyrase than piroxicam (IC = 6.21 µM) in the range of 1.9-1.7-folds. The in vitro antiproliferative activity depicted that all investigated complexes showed better cytotoxic effect than piroxicam, specifically Pt and Pd complexes which had lower IC values than piroxicam on human liver cancer cell line HepG2 by 1.8 and 1.7-folds, respectively. While Pd and Ag complexes showed 2 and 1.6-folds better effect on human colon cancer cell line HT-29 compared with piroxicam. Molecular modeling studies including docking on Stranded DNA Duplex (1juu) and DNA gyrase enzyme (1kzn) that gave good insight about interaction of complexes with target molecules, calculation of electrostatic potential map and global reactivity descriptors were performed.
Topics: Humans; Piroxicam; Coordination Complexes; DNA Gyrase; Anti-Bacterial Agents; Antineoplastic Agents; Microbial Sensitivity Tests; Molecular Docking Simulation
PubMed: 38355931
DOI: 10.1002/ddr.22156 -
International Journal of Biological... Apr 2024Co-precipitation method was adopted to synthesize ternary heterostructure catalysts La/CS-CoSe NSs (lanthanum/chitosan‑cobalt selenide nanostructures) without the use...
Co-precipitation method was adopted to synthesize ternary heterostructure catalysts La/CS-CoSe NSs (lanthanum/chitosan‑cobalt selenide nanostructures) without the use of a surfactant. During synthesis, a fixed amount (3 wt%) of CS was doped with 2 and 4 wt% La to control the growth, recombination rate and stability of CoSe NSs. The doped samples served to enhance the surface area, porosity and active sites for catalytic degradation of rhodamine B dye and antibacterial potential against Staphylococcus aureus (S. aureus). Additionally, the synthesized catalysts were examined for morphological, structural and optical characteristics to assess the influence of dopants to CoSe. XRD spectra verified the hexagonal and cubic structure of CoSe, whereas the porosity of the undoped sample (CoSe) increased from 45 to 60 % upon incorporation of dopants (La and Cs). Among the samples analyzed during this study, 4 % La/CS-CoSe exhibited significant bactericidal behavior as well as the highest catalytic reduction of rhodamine B dye in a neutral environment. Molecular docking analysis was employed to elucidate the underlying mechanism behind the bactericidal activity exhibited by CS-CoSe and La/CS-CoSe NSs against DHFR and DNA gyrase.
Topics: Molecular Docking Simulation; Chitosan; Staphylococcus aureus; Anti-Bacterial Agents; Cobalt; Nanostructures
PubMed: 38354925
DOI: 10.1016/j.ijbiomac.2024.130096 -
Journal of Biomolecular Structure &... Feb 2024Flavonoids demonstrate beneficial effects on human health because flavonoids contain important biological properties. Kaempferol is a flavonol, type of flavonoid found...
Flavonoids demonstrate beneficial effects on human health because flavonoids contain important biological properties. Kaempferol is a flavonol, type of flavonoid found in eatable plants and in plants usually employed in ancient drugs (, Tilia spp., fern genus spp. and gingko etc.). Some medicinal studies have shown that the use of foods full of kaempferol decreases the risk of many (cancer, vascular) diseases. All the data of 50 kaempferol derivatives were collected from PubChem database. Through Schrödinger software, 3D-QSAR study was performed for 50 compounds by using method of field base. Conformer of kaempferol derivatives was docked against anti-diabetic, anti-microbial co-crystal structures and protein. To monitor the best anti-diabetic and antibacterial agent, particular kaempferol derivatives were downloaded from PubChem database. Virtual screening by molecular docking provided four lead compounds with four different proteins. These hit compounds were found to be potent inhibitor for diabetic enzymes alpha-amylase and DPP IV and had the potential to suppress DNA gyrase and dihydrofolate reductase synthesis. Molecular dynamic simulation of docked complexes evaluates the value of root mean square fluctuation by iMOD server. Kaempferol 3-O-alpha-L-(2, 3-di-Z-p-coumaroyl) rhamnoside compound used as anti-diabetic and kaempferol 3-O-gentiobioside as antibacterial with good results can be used for drug discovery.Communicated by Ramaswamy H. Sarma.
PubMed: 38334277
DOI: 10.1080/07391102.2024.2308773