Mechanisms by which small molecules of diverse chemotypes arrest Sec14 lipid transfer activity.

Phosphatidylinositol (PtdIns) transfer proteins (PITPs) enhance the activities of PtdIns 4-OH kinases that generate signaling pools of PtdIns-4-phosphate. In that capacity, PITPs serve as key regulators of lipid signaling in eukaryotic cells. Although the PITP phospholipid exchange cycle is the engine that stimulates PtdIns 4-OH kinase activities, the underlying mechanism is not understood. Herein, we apply an integrative structural biology approach to investigate interactions of the yeast PITP Sec14 with small-molecule inhibitors (SMIs) of its phospholipid exchange cycle. Using a combination of X-ray crystallography, solution NMR spectroscopy, and atomistic MD simulations, we dissect how SMIs compete with native Sec14 phospholipid ligands and arrest phospholipid exchange. Moreover, as Sec14 PITPs represent new targets for the development of next-generation antifungal drugs, the structures of Sec14 bound to SMIs of diverse chemotypes reported in this study will provide critical information required for future structure-based design of next-generation lead compounds directed against Sec14 PITPs of virulent fungi.

Production, optimization and characterization of partially purified anti-mycotic compound from marine soil derived streptomycetes originating at unexplored region of Bay of Bengal, India.

Sixty-eight morphologically distinct isolates of marine actinomycetes were derived from seashore, mangrove, and saltpan ecosystems located between the Palk Strait and Gulf of Mannar region, Bay of Bengal, Tamilnadu. Twenty-five (36.8%) isolates exhibited anti-mycotic activity against Candida albicans and Cryptococcus neoformans in preliminary screening, and 4 isolates with prominent activity were identified and designated at the genus level as Streptomyces sp. VPTS3-I, Streptomyces sp. VPTS3-2, Streptomyces sp. VPTSA1-4 and Streptomyces sp. VPTSA1-8. All the potential antagonistic isolates were further characterized with phenotypic and genotypic properties including 16S rRNA gene sequencing and identified species level as Streptomyces afghaniensis VPTS3-1, S. matensis VPTS3-2, S. tuirus VPTSA1-4 and S. griseus VPTSA1-8. In addition, the active fractions from the potential antagonistic streptomycetes were extracted with organic solvents by shake flask culture method and the anti-mycotic efficacies were evaluated. The optimization parameters for the production of the anti-mycotic compound were found to be pH between 7 and 8, the temperature at 30ᵒC, the salinity of 2%, incubation of 9 days, and starch and KNO3 as the suitable carbon and nitrogen sources respectively in starch casein medium.

Microfluidizing Technique Application for Algerian Cymbopogon citratus (DC.) Stapf Effects Enhanced Volatile Content, Antimicrobial, and Anti-Mycotoxigenic Properties.

Medicinal plant extracts are a promising source of bioactive minor contents. The present study aimed to evaluate the distinguished volatile content of Algerian Cymbopogon citratus (DC.) Stapf before and after the microfluidization process and their related antimicrobial and anti-mycotoxigenic impacts and changes. The GC-MS apparatus was utilized for a comparative examination of Algerian lemongrass essential oil (LGEO) with its microfluidization nanoemulsion (MF-LGEO) volatile content. The MF-LGEO was characterized using Zetasizer and an electron microscope. Cytotoxicity, antibacterial, and antifungal activities were determined for the LGEO and MF-LGEO. The result reflected changes in the content of volatiles for the MF-LGEO. The microfluidizing process enhanced the presence of compounds known for their exceptional antifungal and antibacterial properties in MF-LGEO, namely, neral, geranial, and carvacrol. However, certain terpenes, such as camphor and citronellal, were absent, while decanal, not found in the raw LGEO, was detected. The droplet diameter was 20.76 ± 0.36 nm, and the polydispersity index (PDI) was 0.179 ± 0.03. In cytotoxicity studies, LGEO showed higher activity against the HepG2 cell line than MF-LGEO. Antibacterial LGEO activity against Gram-positive bacteria recorded an inhibitory zone from 41.82 ± 2.84 mm to 58.74 ± 2.64 mm, while the zone ranged from 12.71 ± 1.38 mm to 16.54 ± 1.42 mm for Gram-negative bacteria. Antibacterial activity was enhanced to be up to 71.43 ± 2.54 nm and 31.54 ± 1.01 nm for MF-LGEO impact against Gram-positive and Gram-negative pathogens. The antifungal effect was considerable, particularly against Fusarium fungi. It reached 17.56 ± 1.01 mm and 13.04 ± 1.37 mm for LGEO and MF-LGEO application of a well-diffusion assay, respectively. The MF-LGEO was more promising in reducing mycotoxin production in simulated fungal growth media due to the changes linked to essential compounds content. The reduction ratio was 54.3% and 74.57% for total aflatoxins (AFs) and ochratoxin A (OCA) contents, respectively. These results reflect the microfluidizing improvement impact regarding the LGEO antibacterial, antifungal and anti-mycotoxigenic properties.

Emerging Virulence, Drug Resistance and Future Anti-fungal Drugs for Candida Pathogens.

Increased incidences of Candida infection have augmented morbidity and mortality in human population, particularly among severely immunocompromised patients and those having a long stay in hospitals (nosocomial infections). Many virulence factors and fitness attributes are reported to be associated with the pathogenicity of Candida sp. It can cause infections ranging from easily treatable superficial type to life-threatening invasive infections. Additionally, it has the capability to infect humans of all age groups. Indeed, overutilization of broad-spectrum antibiotics has further complicated the scenario by leading the emergence of less sensitive Candida strains especially non-albicans. Despite our developed armamentarium, the diagnosis and treatment of human fungal infections remain a challenge. This review focuses on the prevalence of Candida spp. as human pathogens with emerging resistance to existing anti-fungal drugs. Furthermore, factors and mechanisms contributing to the pathogenicity of Candida spp. and the challenges being faced in combating the devastating infections associated with these pathogens have been discussed. Moreover, pros and cons of the current and future anti-mycotic drugs have been analyzed.

Newer patents in antimycotic therapy.

There has been a global upsurge in fungal infections due to rise in immunodeficiencies, debilitation and situations of violated anatomical barriers. The available antifungal repertoire has limited activity and is fraught with toxicity concerns. Drug resistance has also shown a rapid upward trend. This has resulted in increased treatment failures, mortality and health care costs. Novel effective and safe antimycotics are needed. Analogues of existing antifungal compounds and new molecules are being developed. New targets are being explored for their putative role in curtailing fungal infections. Newer antigens as vaccine candidates are being researched into. Focused efforts in this direction have yielded encouraging results. This review illuminates the various antifungal strategies which hold promise for the future.

Anti-Mycotic Activity of Garlic Extracts and Extract Fractions in vitro and in planta.

This study was designed to evaluate the inhibitory effects of garlic extracts on the growth of pathogenic molds in planta, using cherry tomatoes as the test commodity. As expected, aqueous and ethanolic extracts of garlic were inhibitory in vitro to a wide range of molds previously isolated from contaminated produce. The extracts were only moderately effective at reducing lesion diameter caused by the growth of two Alternaria spp. Several attempts to further isolate the active inhibitor by solid phase extraction were not successful. These results suggest that despite the effectiveness of garlic as a mold inhibitor in vitro, the whole garlic extract is only moderately effective inhibitor in planta.