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International Journal of Molecular... Mar 2024This study presents the synthesis of four series of novel hybrid chalcones ()- and ()- and six series of 1,3,5-triazine-based pyrimido[4,5-][1,4]diazepines (-)- and the...
Synthesis of Novel Triazine-Based Chalcones and 8,9-dihydro-7-pyrimido[4,5-][1,4]diazepines as Potential Leads in the Search of Anticancer, Antibacterial and Antifungal Agents.
This study presents the synthesis of four series of novel hybrid chalcones ()- and ()- and six series of 1,3,5-triazine-based pyrimido[4,5-][1,4]diazepines (-)- and the evaluation of their anticancer, antibacterial, antifungal, and cytotoxic properties. Chalcones ,, ,, ,-, - and the pyrimido[4,5-][1,4]diazepines ,, , ,,-, ,,- exhibited outstanding anticancer activity against a panel of 60 cancer cell lines with GI values between 0.01 and 100 μM and LC values in the range of 4.09 μM to >100 μM, several of such derivatives showing higher activity than the standard drug 5-fluorouracil (5-FU). On the other hand, among the synthesized compounds, the best antibacterial properties against , (ATCC 43300), and were exhibited by the pyrimido[4,5-][1,4]diazepines (MICs: 0.25-62.5 µg/mL). The antifungal activity studies showed that triazinylamino-chalcone and triazinyloxy-chalcone were the most active compounds against and and , respectively (MICs = 62.5 μg/mL). Hemolytic activity studies and in silico toxicity analysis demonstrated that most of the compounds are safe.
Topics: Chalcones; Antifungal Agents; Staphylococcus aureus; Anti-Bacterial Agents; Azepines; Fluorouracil; Mycobacterium tuberculosis; Neisseria gonorrhoeae; Triazines; Isocyanates
PubMed: 38612435
DOI: 10.3390/ijms25073623 -
The Journal of Antimicrobial... Mar 2024Linezolid exposure in critically ill patients is associated with high inter-individual variability, potentially resulting in subtherapeutic antibiotic exposure....
BACKGROUND
Linezolid exposure in critically ill patients is associated with high inter-individual variability, potentially resulting in subtherapeutic antibiotic exposure. Linezolid exhibits good penetration into the CSF, but its penetration into cerebral interstitial fluid (ISF) is unknown.
OBJECTIVES
To determine linezolid penetration into CSF and cerebral ISF of neurointensive care patients.
PATIENTS AND METHODS
Five neurocritical care patients received 600 mg of linezolid IV twice daily for treatment of extracerebral infections. At steady state, blood and CSF samples were collected from arterial and ventricular catheters, and microdialysate was obtained from a cerebral intraparenchymal probe.
RESULTS
The median fAUC0-24 was 57.6 (24.9-365) mg·h/L in plasma, 64.1 (43.5-306.1) mg·h/L in CSF, and 27.0 (10.7-217.6) mg·h/L in cerebral ISF. The median penetration ratio (fAUCbrain_or_CSF/fAUCplasma) was 0.5 (0.25-0.81) for cerebral ISF and 0.92 (0.79-1) for CSF. Cerebral ISF concentrations correlated well with plasma (R = 0.93, P < 0.001) and CSF levels (R = 0.93, P < 0.001).The median fAUC0-24/MIC ratio was ≥100 in plasma and CSF for MICs of ≤0.5 mg/L, and in cerebral ISF for MICs of ≤0.25 mg/L. The median fT>MIC was ≥80% of the dosing interval in CSF for MICs of ≤0.5 mg/L, and in plasma and cerebral ISF for MICs of ≤0.25 mg/L.
CONCLUSIONS
Linezolid demonstrates a high degree of cerebral penetration, and brain concentrations correlate well with plasma and CSF levels. However, substantial variability in plasma levels, and thus cerebral concentrations, may result in subtherapeutic tissue concentrations in critically ill patients with standard dosing, necessitating therapeutic drug monitoring.
Topics: Humans; Linezolid; Critical Illness; Brain; Anti-Bacterial Agents; Plasma; Isocyanates
PubMed: 38323369
DOI: 10.1093/jac/dkae025 -
Journal of Infection and Chemotherapy :... Jan 2024Zifanocycline (KBP-7072) is a novel aminomethylcycline antibiotic with a broad spectrum of antibacterial activity. This study determined the pharmacokinetic (PK) and...
In vivo efficacy and PK/PD analyses of zifanocycline (KBP-7072), an aminomethylcycline antibiotic, against Acinetobacter baumannii in a neutropenic murine thigh infection model.
INTRODUCTION
Zifanocycline (KBP-7072) is a novel aminomethylcycline antibiotic with a broad spectrum of antibacterial activity. This study determined the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of zifanocycline in mice and the optimal PK/PD index for efficacy against Acinetobacter baumannii in a neutropenic murine thigh infection model.
METHODS
Zifanocycline PK properties were characterized in plasma after single-dose subcutaneous injection in healthy mice at doses of 1, 4, 16, 64, and 256 mg/kg. PK/PD analyses were performed with zifanocycline against 8 clinical A. baumannii isolates in a neutropenic murine thigh infection model.
RESULTS
Plasma total and free drug C, AUC, and AUC increased with dose, where C of total drug was 0.12-25.2 mg/L, AUC was 1.13-234 h*mg/L, AUC was 1.09-225 h*mg/L, and free drug C was 0.03-5.68 mg/L, AUC was 0.25-52.6 h*mg/L, and AUC was 0.25-50.5 h*mg/L. MICs of zifanocycline against A. baumannii ranged from 0.06 to 0.5 mg/L, with significant activity against all 8 strains. Average daily doses of zifanocycline to achieve a static, 1-log kill, and 2-log kill effect were projected to be 6.92, 9.63, and 13.22 mg/kg, and the mean fAUC/MIC ratios were 6.91, 9.10, and 12.60, respectively. AUC/MIC was the optimal PK/PD index of zifanocycline against A. baumannii.
CONCLUSION
The in vivo efficacy results and PK/PD analyses support the design of optimal dosing regimens in clinical studies and assist with determining clinical breakpoints for zifanocycline.
Topics: Animals; Mice; Thigh; Acinetobacter baumannii; Anti-Bacterial Agents; Neutropenia; Communicable Diseases
PubMed: 37714267
DOI: 10.1016/j.jiac.2023.09.010 -
The Journal of Antimicrobial... Sep 2023Imipenem/funobactam (formerly XNW4107) is a novel β-lactam/β-lactamase inhibitor with activity against MDR Acinetobacter baumannii, Pseudomonas aeruginosa and...
Imipenem/funobactam (formerly XNW4107) in vivo pharmacodynamics against serine carbapenemase-producing Gram-negative bacteria: a novel modelling approach for time-dependent killing.
BACKGROUND
Imipenem/funobactam (formerly XNW4107) is a novel β-lactam/β-lactamase inhibitor with activity against MDR Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacterales strains. Using a neutropenic murine thigh infection model, we aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) index, relative to funobactam exposure, that correlated most closely with the in vivo efficacy of imipenem/funobactam combination and the magnitude of index required for efficacy against serine carbapenemase-producing clinical strains.
METHODS
Dose-fractionation was conducted against three strains. Imipenem human-simulated regimen (HSR, 500 mg q6h 1 h infusion) efficacy in combination with escalating funobactam exposures against seven A. baumannii, four P. aeruginosa and four Klebsiella pneumoniae (imipenem/funobactam MICs 0.25-16 mg/L) was assessed as 24 h change in log10cfu/thigh.
RESULTS
Increased funobactam fractionation enhanced efficacy, indicating time-dependent killing. Changes in log10cfu/thigh versus %fT > MIC were poorly predictive of efficacy; bactericidal activity was observed at %fT > MIC = 0%. Across different threshold plasma funobactam concentrations (CTs), %fT > CT(1 mg/L) had the highest correlation with efficacy. Normalizing the %fT > CT = 1 mg/L index to the respective isolate imipenem/funobactam MIC ([%fT > CT]/MIC) allowed integration of the isolate's susceptibility, which further enhanced the correlation. Median (%fT > CT[1 mg/L])/MIC values associated with 1-log reductions were 9.82 and 9.90 for A. baumannii and P. aeruginosa, respectively. Median (%fT > CT[1 mg/L])/MIC associated with stasis was 55.73 for K. pneumoniae. Imipenem/funobactam 500/250 mg q6h 1 h infusion HSR produced >1-log kill against 6/7 A. baumannii, 4/4 P. aeruginosa and stasis against 4/4 K. pneumoniae.
CONCLUSIONS
Imipenem/funobactam showed potent in vivo efficacy against serine carbapenemase-producers. The novel PK/PD index (%fT > CT)/MIC appeared to best describe in vivo activity.
Topics: Humans; Animals; Mice; Imipenem; Bacteria; Bacterial Proteins; Neutropenia; Acinetobacter baumannii; Klebsiella pneumoniae
PubMed: 37667103
DOI: 10.1093/jac/dkad242 -
Frontiers in Cellular and Infection... 2023This study aimed to investigate sudapyridine (WX-081) antibacterial activity against and its effect on bacterial growth and host survival using a zebrafish model of...
OBJECTIVE
This study aimed to investigate sudapyridine (WX-081) antibacterial activity against and its effect on bacterial growth and host survival using a zebrafish model of infection.
METHODS
WX-081 antibacterial activity was assessed based on growth inhibition of standard strain ATCC19977 and 36 clinical isolates. Maximum tolerated concentrations (MTCs) of WX-081, bedaquiline, and azithromycin and inhibition of growth were assessed after fluorescently labelled bacilli and drugs were injected into zebrafish. Bacterial counts were analysed using one-way ANOVA and fluorescence intensities of zebrafish tissues were analysed and expressed as the mean ± SE. Moreover, Kaplan-Meier survival analysis was conducted to assess intergroup differences in survival of -infected zebrafish treated with different drug concentrations using a log-rank test, with a p value <0.05 indicating a difference was statistically significant.
RESULTS
Drug sensitivity testing of standard strain ATCC19977 and 36 clinical isolates revealed MICs ranging from 0.12-0.96 µg/mL and MIC and MIC values of 0.48 µg/mL and 0.96 µg/mL, respectively. Fluorescence intensities of -infected zebrafish tissues was lower after treatment with the WX-081 MTC (62.5 µg/mL) than after treatment with the azithromycin MTC (62.5 µg/mL) and the bedaquiline MTC (15.6 µg/mL). When the concentration of WX-081 increased from 1.95µg/mL to 1/8 MTC(7.81µg/mL), the survival rate of zebrafish at 4-9 dpf decreased from 90.00% to 81.67%.
CONCLUSION
WX-081 effectively inhibited growth and and prolonged survival of -infected zebrafish, thus indicating that WX-081 holds promise as a clinical treatment for infection.
Topics: Animals; Azithromycin; Mycobacterium abscessus; Zebrafish; Anti-Bacterial Agents
PubMed: 37662015
DOI: 10.3389/fcimb.2023.1217975 -
Molecules (Basel, Switzerland) Aug 2023We report herein the synthesis, docking studies and biological evaluation of a series of new 4-chloro-2-((5-aryl-1,3,4-oxadiazol-2-yl)amino)phenol analogues (). The new...
We report herein the synthesis, docking studies and biological evaluation of a series of new 4-chloro-2-((5-aryl-1,3,4-oxadiazol-2-yl)amino)phenol analogues (). The new compounds were designed based on the oxadiazole-linked aryl core of tubulin inhibitors of IMC-038525 and IMC-094332, prepared in five steps and further characterized via spectral analyses. The anticancer activity of the compounds was assessed against several cancer cell lines belonging to nine different panels as per National Cancer Institute (NCI US) protocol. 4-Chloro-2-((5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazol-2-yl)amino)phenol () demonstrated significant anticancer activity against SNB-19 (PGI = 65.12), NCI-H460 (PGI = 55.61), and SNB-75 (PGI = 54.68) at 10 µM. The compounds were subjected to molecular docking studies against the active site of the tubulin-combretastatin A4 complex (PDB ID: 5LYJ); they displayed efficient binding and ligand (with docking score = -8.030 kcal/mol) lay within the hydrophobic cavity surrounded by important residues Leu252, Ala250, Leu248, Leu242, Cys241, Val238, Ile318, Ala317, and Ala316. Furthermore, the antibacterial activity of some of the compounds was found to be promising. 4-Chloro-2-((5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)amino)phenol () displayed the most promising antibacterial activity against both Gram-negative as well as Gram-positive bacteria with MICs of 8 µg/mL and a zone of inhibition ranging from 17.0 ± 0.40 to 17.0 ± 0.15 mm at 200 µg/mL; however, the standard drug ciprofloxacin exhibited antibacterial activity with MIC values of 4 µg/mL.
Topics: Phenol; Molecular Docking Simulation; Phenols; Anti-Bacterial Agents
PubMed: 37630338
DOI: 10.3390/molecules28166086 -
Antimicrobial Agents and Chemotherapy Sep 2023Development of new therapeutics against antibiotic resistant pathogenic bacteria is recognized as a priority across the globe. We have reported using peptide-conjugated...
Development of new therapeutics against antibiotic resistant pathogenic bacteria is recognized as a priority across the globe. We have reported using peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) as species-specific antibiotics. The oligo sequences, 11 bases are designed to be complementary to specific essential genes near the Shine-Dalgarno site and inhibit translation. Here, we analyzed target specificity and the impact of genetic mutations on lead PPMOs targeting the or gene of . Mutants in PAO1 were generated with four, two, or one base-pair mutations within the 11-base target sequence of the gene. All mutants exhibited increased MICs compared to wild-type PAO1 when treated with the RpsJ PPMO, and the increase in the MICs was proportional to the number of base-pair mutations. Among single base-pair mutants, mutations in the middle of the sequence were more impactful than mutations in 5' or 3' end of the sequence. The increased MICs shown by the mutants could be reversed by PPMOs designed to target the mutated sequence. BALB/c mice infected intratracheally with mutants demonstrated increased lung burden when treated with RpsJ PPMO compared to wild-type PAO1-infected mice treated with RpsJ PPMO. Treating mice with a PPMOs designed to specifically target the mutant sequence was more effective against these mutant strains. These experiments confirm target specificity of two lead PPMOs and illustrate one potential mechanism of resistance that could emerge from an antisense approach.
Topics: Animals; Mice; Morpholinos; Pseudomonas aeruginosa; Anti-Bacterial Agents; Genes, Essential; Mice, Inbred BALB C
PubMed: 37610213
DOI: 10.1128/aac.00245-23