Currently browsing

marzo 30, 2021

Repurposing celecoxib analogues as leads for antibiotics

There is an urgent need for new antibiotics and alternative strategies to combat bacterial pathogens. Molecular docking, antibacterial evaluation in vitro and in vivo, cytotoxicity assessment and enzyme inhibition analyses were performed. Compound 12 exhibited antimicrobial activity against Staphylococcus aureus (MIC: 4 μg/ml), various clinically isolated strains of MRSA (MIC: 4-16 μg/ml) and Acinetobacter baumannii (MIC: 4 μg/ml) when combined with subinhibitory concentrations of colistin B….

Emergence of resistance to ceftazidime-avibactam in a derepressed bla (PDC) producing Pseudomonas aeruginosa isolate in a Hollow Fiber Infection Model

Ceftazidime/Avibactam (CAZ/AVI) is a β-lactam/β-lactamase inhibitor combination with activity against type A and C β-lactamases. Resistance emergence has been seen with multiple mechanisms accounting for the resistance. We performed four experiments in the dynamic Hollow Fiber Infection Model, delineating the linkage between drug exposure and both rate of bacterial kill and resistance emergence by all mechanisms. The P. aeruginosa isolate had an MIC of 1.0 mg/L (CAZ)/4 mg/L (AVI). We…

Total Syntheses and Chemical Biology Studies of Hymeglusin and Fusarilactone A, Novel Circumventors of beta-Lactam Drug Resistance in Methicillin-Resistant Staphylococcus aureus

Hymeglusin, a previously known eukaryotic hydroxymethylglutaryl-CoA (HMG-CoA) synthase inhibitor, was identified as circumventing the β -lactam drug resistance in methicillin-resistant Staphylococcus aureus (MRSA). We describe the concise total syntheses of a series of natural products, which enabled determination of the absolute configuration of fusarilactone A and provided structure-activity relationship information. Based on previous reports, we speculated that the target protein of this…

Efficacy and Associated Drug Exposures of Isavuconazole and Fluconazole in an Experimental Model of Coccidioidomycosis

Coccidioides spp. are important pathogens in endemic regions and new treatment options are needed. Isavuconazonium sulfate (ISAVUSULF) and fluconazole (FLU) were evaluated in experimental disseminated coccidioidomycosis to characterize drug exposures associated with efficacy.Macrobroth dilution was performed on Coccidioides isolates to measure minimal effective concentrations (MEC) and minimal fungicidal concentrations (MFC). Mice were inoculated with Coccidioides posadasii (Silveira strain)….

In Vitro Activity of the Ultra-Broad-Spectrum Beta-lactamase Inhibitor QPX7728 in Combination with Multiple Beta-Lactam Antibiotics against Pseudomonas aeruginosa

QPX7728 is an ultra-broad-spectrum beta-lactamase inhibitor with potent inhibition of key serine and metallo beta-lactamases. QPX7728 enhances the potency of multiple beta-lactams in beta-lactamase producing Enterobacterales and Acinetobacter spp. In this study we evaluated the in vitro activity of QPX7728 (8 μg/ml) combined with multiple beta-lactams against clinical isolates of Pseudomonas aeruginosa with varying beta-lactam resistance mechanisms.Seven-hundred-ninety clinical isolates were…

Concomitant Administration of posaconazole and isavuconazole with Letermovir: Clinical and Pharmacological Considerations

We sought in this case-control retrospective study to compare posaconazole/isavuconazole (PCZ/IVC)-C(trough) in high-risk allogeneic hematopoietic cell transplant (HCT) recipients who received letermovir (LET) or not. PCZ/IVC-C(trough) were not found to be significantly different between cases and controls: 1.31 mg/l (median) (0.90; IQR) vs 1.36 mg/l (1.16) (P-value: 0.31) and 3.20 mg/l (2.40) vs 2.35 mg/l (1.50) (P-value: 0.17), respectively. In conclusion, we observed PCZ/IVC-C(trough) levels…

Detection of extended spectrum beta-lactamase genes in Pseudomonas aeruginosa isolated from patients in rural Eastern Cape Province, South Africa

The proliferation of extended spectrum beta-lactamase (ESBL) producing Pseudomonas aeruginosa represent a major public health threat. In this study, we evaluated the antimicrobial resistance patterns of P. aeruginosa strains and characterized the ESBLs and Metallo- β-lactamases (MBL) produced. Strains of P. aeruginosa cultured from patients who attended Nelson Mandela Academic Hospital and other clinics in the four district municipalities of the Eastern Cape between August 2017 and May 2019 were…

A novel GSH-triggered polymeric nanomicelles for reversing MDR and enhancing antitumor efficiency of Hydroxycamptothecin

Tumor multidrug resistance (MDR) is one of the main reasons for the failure of clinical chemotherapy. Here, a bio-responsive anti-drug-resistant polymer micelle that can respond to the reductive GSH in the tumor microenvironment (TME) for delivery of HCPT was designed. A new type of with anti-drug resistance and anti-tumor effect was synthesized and used to encapsulated HCPT to form reduction-sensitive micelles (PDSAH) by a thin-film dispersion method. It is demonstrated that the micelle…

Pharyngeal microbial signatures are predictive of the risk of fungal pneumonia in hematologic patients

The ability to predict invasive fungal infections (IFI) in patients with hematological malignancies is fundamental for successful therapy. Although gut dysbiosis is known to occur in hematological patients, whether airways dysbiosis also contributes to the risk of IFI has not been investigated. Nasal and oropharyngeal swabs were collected for functional microbiota characterization in 173 patients with hematological malignancies recruited in a multicenter, prospective, observational study and…