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PloS One 2024Mucosal-delivered drugs have to pass through the mucus layer before absorption through the epithelial cell membrane. Although there has been increasing interest in...
Mucosal-delivered drugs have to pass through the mucus layer before absorption through the epithelial cell membrane. Although there has been increasing interest in polymeric mucins, a major structural component of mucus, potentially acting as important physiological regulators of mucosal drug absorption, there are no reports that have systematically evaluated the interaction between mucins and drugs. In this study, we assessed the potential interaction between human polymeric mucins (MUC2, MUC5B, and MUC5AC) and various drugs with different chemical profiles by simple centrifugal method and fluorescence analysis. We found that paclitaxel, rifampicin, and theophylline likely induce the aggregation of MUC5B and/or MUC2. In addition, we showed that the binding affinity of drugs for polymeric mucins varied, not only between individual drugs but also among mucin subtypes. Furthermore, we demonstrated that deletion of MUC5AC and MUC5B in A549 cells increased the cytotoxic effects of cyclosporin A and paclitaxel, likely due to loss of mucin-drug interaction. In conclusion, our results indicate the necessity to determine the binding of drugs to mucins and their potential impact on the mucin network property.
Topics: Humans; Paclitaxel; Mucin 5AC; A549 Cells; Drug Interactions; Mucin-5B; Mucins; Mucin-2; Rifampin; Cyclosporine; Protein Binding
PubMed: 38935605
DOI: 10.1371/journal.pone.0306058 -
MBio Jun 2024Contemporary antifungal therapies utilized to treat filamentous fungal infections are inhibited by intrinsic and emerging drug resistance. Consequently, there is an...
Contemporary antifungal therapies utilized to treat filamentous fungal infections are inhibited by intrinsic and emerging drug resistance. Consequently, there is an urgent need to develop novel antifungal compounds that are effective against drug-resistant filamentous fungi. Here, we utilized an cell-based high-throughput screen to identify small molecules with antifungal activity that also potentiated triazole activity. The screen identified 16 hits with promising activity against . A nonspirocyclic piperidine, herein named MBX-7591, exhibited synergy with triazole antifungal drugs and activity against pan-azole-resistant isolates. MBX-7591 has additional potent activity against species and CO-dependent activity against . Chemical, genetic, and biochemical mode of action analyses revealed that MBX-7591 increases cell membrane saturation by decreasing oleic acid content. MBX-7591 has low toxicity and shows good efficacy in decreasing fungal burden in a murine model of invasive pulmonary aspergillosis. Taken together, our results suggest MBX-7591 is a promising hit with a novel mode of action for further antifungal drug development to combat the rising incidence of triazole-resistant filamentous fungal infections.IMPORTANCEThe incidence of infections caused by fungi continues to increase with advances in medical therapies. Unfortunately, antifungal drug development has not kept pace with the incidence and importance of fungal infections, with only three major classes of antifungal drugs currently available for use in the clinic. Filamentous fungi, also called molds, are particularly recalcitrant to contemporary antifungal therapies. Here, a recently developed cell reporter strain was utilized to conduct a high-throughput screen to identify small molecules with antifungal activity. An emphasis was placed on small molecules that potentiated the activity of contemporary triazole antifungals and led to the discovery of MBX-7591. MBX-7591 potentiates triazole activity against drug-resistant molds such as and has activity against Mucorales fungi. MBX-7591's mode of action involves inhibiting the conversion of saturated to unsaturated fatty acids, thereby impacting fungal membrane integrity. MBX-7591 is a novel small molecule with antifungal activity poised for lead development.
PubMed: 38934618
DOI: 10.1128/mbio.01166-24 -
Viruses Jun 2024Lipids, as a fundamental cell component, play an regulating role in controlling the different cellular biological processes involved in viral infections. A notable...
BACKGROUND
Lipids, as a fundamental cell component, play an regulating role in controlling the different cellular biological processes involved in viral infections. A notable feature of coronavirus disease 2019 (COVID-19) is impaired lipid metabolism. The function of lipophagy-related genes in COVID-19 is unknown. The present study aimed to investigate biomarkers and drug targets associated with lipophagy and lipophagy-based therapeutic agents for COVID-19 through bioinformatics analysis.
METHODS
Lipophagy-related biomarkers for COVID-19 were identified using machine learning algorithms such as random forest, Support Vector Machine-Recursive Feature Elimination, Generalized Linear Model, and Extreme Gradient Boosting in three COVID-19-associated GEO datasets: scRNA-seq (GSE145926) and bulk RNA-seq (GSE183533 and GSE190496). The cMAP database was searched for potential COVID-19 medications.
RESULTS
The lipophagy pathway was downregulated, and the lipid droplet formation pathway was upregulated, resulting in impaired lipid metabolism. Seven lipophagy-related genes, including , , , , , , and , were used as biomarkers and drug targets for COVID-19. Moreover, lipophagy may play a role in COVID-19 pathogenesis. As prospective drugs for treating COVID-19, seven potential downregulators (phenoxybenzamine, helveticoside, lanatoside C, geldanamycin, loperamide, pioglitazone, and trichostatin A) were discovered. These medication candidates showed remarkable binding energies against the seven biomarkers.
CONCLUSIONS
The lipophagy-related genes , , , , , , and can be used as biomarkers and drug targets for COVID-19. Seven potential downregulators of these seven biomarkers may have therapeutic effects for treating COVID-19.
Topics: Humans; SARS-CoV-2; COVID-19 Drug Treatment; Biomarkers; COVID-19; Lipid Metabolism; Antiviral Agents; Computational Biology; Machine Learning; Lactams, Macrocyclic; Hydroxamic Acids; Benzoquinones
PubMed: 38932215
DOI: 10.3390/v16060923 -
Polymers Jun 2024The antifungal agent, ketoconazole, and the anti-inflammatory drug, piroxicam, were incorporated into matrices of xanthan or oleic acid-esterified xanthan (Xn) and...
The antifungal agent, ketoconazole, and the anti-inflammatory drug, piroxicam, were incorporated into matrices of xanthan or oleic acid-esterified xanthan (Xn) and polyurethane (PU), to develop topical drug delivery systems. Compared to matrices without bioactive compounds, which only showed a nominal compressive stress of 32.18 kPa (sample xanthan-polyurethane) at a strain of 71.26%, the compressive resilience of the biomaterials increased to nearly 50.04 kPa (sample xanthan-polyurethane-ketoconazole) at a strain of 71.34%. The compressive strength decreased to around 30.67 kPa upon encapsulating a second drug within the xanthan-polyurethane framework (sample xanthan-polyurethane-piroxicam/ketoconazole), while the peak sustainable strain increased to 87.21%. The Weibull model provided the most suitable fit for the drug release kinetics. Unlike the materials based on xanthan-polyurethane, those made with oleic acid-esterified xanthan-polyurethane released the active ingredients more slowly (the release rate constant showed lower values). All the materials demonstrated antimicrobial effectiveness. Furthermore, a higher volume of piroxicam was released from oleic acid-esterified xanthan-polyurethane-piroxicam (64%) as compared to xanthan-polyurethane-piroxicam (44%). Considering these results, materials that include polyurethane and either modified or unmodified xanthan showed promise as topical drug delivery systems for releasing piroxicam and ketoconazole.
PubMed: 38932084
DOI: 10.3390/polym16121734 -
Pharmaceutics Jun 2024Caspofungin is an echinocandin antifungal agent commonly used as the first-line therapy for invasive candidiasis, salvage therapy for invasive aspergillosis, and...
BACKGROUND
Caspofungin is an echinocandin antifungal agent commonly used as the first-line therapy for invasive candidiasis, salvage therapy for invasive aspergillosis, and empirical therapy for presumed fungal infections. Pharmacokinetic (PK) variabilities and suboptimal exposure have been reported for caspofungin, increasing the risk of insufficient efficacy.
OBJECTIVE
This work aimed to develop a caspofungin population pharmacokinetic (popPK) library and demonstrate its utility by assessing the probability of target attainment across diverse settings.
METHODS
We established a caspofungin popPK model library following a rigorous literature review, re-implementing selected models in R with rxode2. Quality control procedures included a comparison of different studies and assessing covariate impacts. Model libraries were primarily used to perform Monte Carlo simulations to estimate target attainment and guide personalized dosing in Candida infections.
RESULTS
A total of 13 models, one- or two-compartment models, were included. The most significant covariates were body size (weight and body surface area), liver function, and albumin level. The results show that children and adults showed considerable differences in pharmacokinetics. For and , none of the populations achieved a PTA of ≥90% at their respective susceptible MIC values. In contrast, for , 70% of the adult studies reached a PTA of ≥90%, while all pediatric studies achieved the same PTA level.
CONCLUSION
At the recommended dosage, adult patients showed notably lower exposure to caspofungin compared to pediatric patients. Considering body size, liver function, and serum albumin is crucial when determining caspofungin dosage regimens. Furthermore, further research is required to comprehensively understand the pharmacokinetics of caspofungin in pediatric patients.
PubMed: 38931940
DOI: 10.3390/pharmaceutics16060819 -
Pharmaceuticals (Basel, Switzerland) Jun 2024A series of hybrid compounds with triazole and thiazolidine nuclei connected by a linker has been synthesized and extensively studied. Various synthetic methods for the...
A series of hybrid compounds with triazole and thiazolidine nuclei connected by a linker has been synthesized and extensively studied. Various synthetic methods for the target compounds have been tested. A microbiological assessment of the obtained compounds was carried out on strains of pathogenic fungi , , multidrug-resistant , , spp. and some dermatophytes and other yeasts. The lowest obtained MIC values for target compounds lie between 0.003 µg/mL and 0.5 µg/mL and therefore the compounds are not inferior or several times better than commercial azole drugs. The length of the acylpiperazine linker has a limited effect on antifungal activity. Some bioisosteric analogues were tested in microbiological analysis, but turned out to be weaker than the leader in activity. The highest activity was demonstrated by a compound with -chlorobenzylidene substituent in the thiazolidine fragment. Molecular modelling was used to predict binding modes of synthesized molecules and rationalize experimentally observed SAR. The leader compound is twice more effective in inhibiting the formation of germ tubes by yeast cells compared to voriconazole. An increased level of Pdr5, an azoles drug efflux pump was observed, but the increase is lower than that caused by azoles. The results can be useful for further development of more powerful and safe antifungal agents.
PubMed: 38931390
DOI: 10.3390/ph17060723 -
Plants (Basel, Switzerland) Jun 2024Recent focus has been given to nanoparticles as an alternative fungicidal compound instead of chemical ones. More environmentally friendly ways of synthesis are the...
Recent focus has been given to nanoparticles as an alternative fungicidal compound instead of chemical ones. More environmentally friendly ways of synthesis are the highest priority regarding the antifungal agents in the agriculture sector. Therefore, in this research, hyssop () and sage () aqueous extracts were prepared and used as a reducing source in the green synthesis of silver nanoparticles (AgNPs). Aqueous extracts and green synthesized AgNPs were examined for phytochemical composition and antioxidant capacity. Hyssop and sage extracts based AgNPs were analyzed using UV-vis spectrometry, SEM-EDS, and TEM-EDS. Antifungal activity against spp. isolates collected from different infected crops was determined. spp. isolates from strawberry, asparagus, pea, carrot, wheat, and rapeseed samples identified at the molecular level by translation elongation factor 1-alpha (TEF1α) gene amplification and sequencing. Green synthesized AgNPs had lower phytochemical content, however higher antioxidant activity compared to pure extracts. Both hyssop and sage extracts are suitable reducing agents for AgNPs formation, and sage extract results in larger particle size. Aqueous hyssop extract had higher antifungal activity than aqueous sage extract. However, a 10% concentration of whole sage extract based AgNPs solution, added to the PDA medium, and a 5% concentration of hyssop extract based AgNPs inhibited spp. the most. was the most sensitive to all treatments among the other fungi.
PubMed: 38931043
DOI: 10.3390/plants13121611 -
Plants (Basel, Switzerland) Jun 2024Species belonging to the genus (Apiaceae) have been used by humanity since ancient times as flavoring agents, preservatives, and medicines for the treatment of a broad... (Review)
Review
Species belonging to the genus (Apiaceae) have been used by humanity since ancient times as flavoring agents, preservatives, and medicines for the treatment of a broad spectrum of conditions, including respiratory, digestive and kidney disorders, fungi infections, wounds, and gastric ulcers. Phytochemical studies on this botanical genus mainly investigate the essential oil composition and reveal the species as a rich source of volatile compounds, including monoterpenes and phenylpropanoids. Among the non-volatile secondary metabolites, flavonoids, coumarins, phenolic acids, phytosterols, and polyacetylenes have been identified. Pharmacological studies revealed extracts and essential oils exhibit different biological properties, including antibacterial, antifungal, anticancer, insecticidal, anti-inflammatory, and hepatoprotective activities. However, compared to other genera, the biological activity and chemical diversity of this genus are not well studied. In future decades, it is highly likely that the small genus will play an important role in drug discovery and drug development.
PubMed: 38931031
DOI: 10.3390/plants13121599 -
Molecules (Basel, Switzerland) Jun 2024Fluconazole (2-(2,4-difluorophenyl)-1,3-bis(1-1,2,4-triazol-1-yl)propan-2-ol), which was patented in 1981 and introduced for commercial use in 1988, is a widely utilized... (Review)
Review
Fluconazole (2-(2,4-difluorophenyl)-1,3-bis(1-1,2,4-triazol-1-yl)propan-2-ol), which was patented in 1981 and introduced for commercial use in 1988, is a widely utilized antifungal drug whose mechanism of action involves inhibition of the activity of 14-α lanosterol demethylase. Its safety and effectiveness have established it as one of the most frequently employed antifungal agents. Resistance to azole antifungal drugs is becoming more common. It may be related to a mutation of the gene encoding the enzyme. To address this issue, molecules with modifications in three main regions of fluconazole, namely the hydroxyl group, the aromatic ring, and the 1,2,4-triazole rings, have been synthesized in an attempt to create more potent antifungal drugs. These modifications aim at enhancing the effectiveness against microorganisms and improving pharmacokinetic parameters and safety profiles of the synthesized compounds. The present review explores the synthesis of fluconazole derivatives, accompanied by insights into the results of biological studies evaluating the therapeutic effects of these compounds.
Topics: Fluconazole; Antifungal Agents; Humans; Structure-Activity Relationship; Microbial Sensitivity Tests; Animals; Drug Resistance, Fungal; Molecular Structure
PubMed: 38930921
DOI: 10.3390/molecules29122855 -
Molecules (Basel, Switzerland) Jun 2024In this work, a group of ten sesquiterpene drimanes, including polygodial (), isopolygodial (), and drimenol () obtained from the bark of F. and seven synthetic...
In this work, a group of ten sesquiterpene drimanes, including polygodial (), isopolygodial (), and drimenol () obtained from the bark of F. and seven synthetic derivatives, were tested in vitro against a unique panel of bacteria, fungi, and oomycetes with standardized procedures against bacterial strains , , , and The minimum inhibitory concentrations and bactericidal activities were evaluated using standardized protocols. Polygodial () was the most active compound, with MBC 8 μg/mL and MIC 16 μg/mL in ; MBC 16 μg/mL and MIC 32 μg/mL in ; MBC 64 μg/mL and MIC 64 μg/mL in ; and MBC 8 μg/mL and MIC 16 μg/mL and MBC 32 μg/mL and MIC 64 μg/mL in , respectively. The observed high potency could be attributed to the presence of an aldehyde group at the C8-C9 position. The antifungal activity of from different microbial isolates has been evaluated. The results show that polygodial affects the growth of normal isolates and against filamentous fungi and oomycetes with MFC values ranging from 8 to 64 μg/mL. Sesquiterpene drimanes isolated from this plant have shown interesting antimicrobial properties.
Topics: Sesquiterpenes; Microbial Sensitivity Tests; Anti-Infective Agents; Drimys; Polycyclic Sesquiterpenes; Anti-Bacterial Agents; Plant Extracts; Escherichia coli; Fungi; Bacteria
PubMed: 38930909
DOI: 10.3390/molecules29122844