Emerging Antifungal Targets and Strategies Ivanov, Marija; Ćirić, Ana; Stojković, Dejan
International journal of molecular sciences,
03/2022, Letnik:
23, Številka:
5
Journal Article
Recenzirano
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Despite abundant research in the field of antifungal drug discovery, fungal infections remain a significant healthcare burden. There is an emerging need for the development of novel antifungals since ...those currently available are limited and do not completely provide safe and secure protection. Since the current knowledge regarding the physiology of fungal cells and the infection mechanisms is greater than ever, we have the opportunity to use this for the development of novel generations of antifungals. In this review, we selected and summarized recent studies describing agents employing different antifungal mechanisms. These mechanisms include interference with fungal resistance, including impact on the efflux pumps and heat shock protein 90. Additionally, interference with virulence factors, such as biofilms and hyphae; the impact on fungal enzymes, metabolism, mitochondria, and cell wall; and antifungal vaccines are explored. The agents investigated belong to different classes of natural or synthetic molecules with significant attention given also to plant extracts. The efficacy of these antifungals has been studied mainly in vitro with some in vivo, and clinical studies are needed. Nevertheless, there is a large quantity of products employing novel antifungal mechanisms that can be further explored for the development of new generation of antifungals.
The increasing incidence of patients struggling with fungal infections, along with high losses in the production of different foods/crops due to fungal diseases presents a significant burden to ...healthcare, agronomy, and economies worldwide ...
•Antimicrobial and antioxidant properties of Greek garlics were evaluated.•Significant variation among the studied genotypes was observed.•Genotype G5 showed the highest total phenolics content and ...the lowest EC50 values.•Significant activity against Proteus mirabilis and Escherichia coli was recorded.•Inhibitory properties against Candida albicans and C. kruzei were detected.
Recent studies show a significant variation in antioxidant and antimicrobial properties between the various garlic genotypes mostly due to differences in chemical composition and bioactive compounds content. The aim of the present study was to evaluate antioxidant properties and antimicrobial activity of garlics collected from the main cultivation areas of Greece, as well as to correlate this activity with their total phenolics content. Genotype G5 showed the highest total phenolics content, which was significantly correlated with the lowest EC50 values for all the tested antioxidant activity assays. Antimicrobial activity was significant, especially against the bacteria Proteus mirabilis and Antibiotic resistant Escherichia coli. In conclusion, significant variation was observed between the studied garlic genotypes, indicating the importance of both growing conditions and genotype on bioactive properties of dry garlic bulbs. This variation could be further exploited in breeding programs in order to select elite genotypes with increased bioactive properties.
This study investigated the combined influence of pH adjusting agent type (hydrochloric, acetic or lactic acid) and initial pH value (3.6, 4.6, and 5.6) on formation of biocompatible chitosan/xanthan ...polyelectrolyte complexes (PECs), their characteristics in solid state and influence on in vitro ibuprofen release kinetics. Conductivity measurements and rheological characterization revealed generally higher extent of ionic interactions in PEC dispersions comprising acetic acid and at pH 3.6. Acid type and pH affected significantly the yield and particle size (100–250 μm) of the dried PECs. Differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), and powder X-ray diffraction (PXRD) analysis of the solid PECs confirmed exclusively physical (ionic, hydrogen bonds) interactions between chitosan and xanthan gum. PECs prepared with acetic acid at pH 4.6 and 5.6 had enhanced rehydration ability in phosphate buffer pH 7.2, and at PEC-to-drug mass ratio up to 1:2, enabled extended ibuprofen release from hard capsules during 10 h.
•Formation and solid state of chitosan/xanthan PECs was characterized.•Higher extent of ionic interactions was noticed in PECs with acetic acid at pH 3.6.•Exclusively physical interactions were confirmed in all solid PECs.•PECs with acetic acid had enhanced rehydration ability in phosphate buffer pH 7.2.•PECs with acetic acid at pH 4.6 and 5.6 enabled extended release of ibuprofen.
The physical chitosan hydrogel, obtained by ionic gelation in lactic acid solution, was combined with biocompatible oil-in-water microemulsion with ibuprofen, to prepare composite hydrogels with ...0.25-1% of the polymer and 5% of the drug. The electrical conductivity measurement, photon correlation spectroscopy (PCS), and rheological analysis showed that the composite hydrogels comprise oil nanodroplets (16.21-22.56 nm) embedded within pseudoplastic chitosan hydrogel. In vitro ibuprofen release was sustained for 12 h and followed zero-order kinetics. pH values of the composite hydrogels were in the range of 4.80-5.27, thus physiologically acceptable. The formulation containing 0.5% chitosan enabled the maximum drug release rate of 239.25 μgh
−1
cm
−2
as well as cohesiveness (154.958 ± 0.731 g*s) higher than hardness (13.546 ± 0.065 g) and adhesiveness (−12.042 ± 1.161 g*s), so textural properties were suitable for application along skin surface, without spillage, and for easy removal. This is the first study in which the composite chitosan hydrogels with ibuprofen were formulated by combining the chitosan hydrogel prepared without harmful chemical crosslinkers and low viscosity oil-in-water microemulsion, and the preclinical characterization of their biopharmaceutical aspect and textural characterization, that is of key importance in improving the patient's compliance, were performed.
•Composition of Diospyros virginiana methanol extract, phenolic profile.•Methanol extract, their isolated phenolic compounds have shown significant antimicrobial effect.•Flavonoid aglycones exhibited ...the strongest antimicrobial activity.
This study was carried out with the objective to investigate antibacterial and antifungal activities of Diospyros virginiana fruits (methanol 80%) extract and the phenolic compounds isolated from the extract. The in vitro antibacterial and antifungal assays were done against eight bacterial strains and against eight fungal species using microdilution method. Eight phenolic compounds, m-gallate, gallic acid, luteolin, quercetin, myricetin, myricetin 3-O-α-rhamnoside, myricetin 3-O-β-glucoside, and myricetin 3-O-β-glucuronide were isolated and identified by different spectroscopic tools (UV, 1H NMR, 13C NMR, MS). The results of the methanol extract of Diospyros virginiana fruits and its isolated phenolic compounds showed significant antibacterial and antifungal effects against all the tested microorganisms. The best results were obtained for flavonoid aglycones which showed strong antimicrobial activity against all the microorganisms tested. These results may help to discover new chemical classes of natural antimicrobial substances that could serve as selective agents for infectious disease chemotherapy and control.
Base catalysed condensation of ketone 5 with different aldehydes give chalcones, 2.4-bis-(phenylamino)-6-4'-{3''-(4'''-substituted ...phenyl/2'''-furanyl/2'''-thienyl)-2''-propenon-1''-yl}phenylamino-s-thriazines 6a-e. These chalcones on cyclization with hydrazine hydrate in the presence of glacial acetic acid, guanidine nitrate in the presence of alkali and malononitrile in the presence of ammonium acetate give the corresponding acetylpyrazolines 7a-e, aminopyrimidines 8a-e and cyanopyridines 9a-e respectively. The products 6a-e, 7a-e, 8a-e and 9a-e were fully characterized by spectroscopic and elemental analysis and also tested for antibacterial activity.
Infectious diseases symbolize a global consequential strain on public health security and impact on the socio-economic stability all over the world. The increasing resistance to the current ...antimicrobial treatment has resulted in crucial need for the discovery and development of novel entity for the infectious treatment with different modes of action that could target both sensitive and resistant strains.
Compounds were synthesized using classical methods of organic synthesis.
All 20 synthesized compounds showed antibacterial activity against eight Gram-positive and Gram-negative bacterial species. It should be mentioned that all compounds exhibited better antibacterial potency than ampicillin against all bacteria tested. Furthermore, 18 compounds appeared to be more potent than streptomycin against
,
and
. Three the most active compounds
,
, and
appeared to be more potent against MRSA than ampicillin, while streptomycin did not show any bactericidal activity. All three compounds displayed better activity also against resistant strains
and
than ampicillin. Furthermore, all compounds were able to inhibit biofilm formation 2- to 4-times more than both reference drugs. Compounds were evaluated also for their antifungal activity against eight species. The evaluation revealed that all compounds exhibited antifungal activity better than the reference drugs bifonazole and ketoconazole. Molecular docking studies on antibacterial and antifungal targets were performed in order to elucidate the mechanism of antibacterial activity of synthesized compounds.
All tested compounds showed good antibacterial and antifungal activity better than that of reference drugs and three the most active compounds could consider as lead compounds for the development of new more potent agents.
Twelve steroid based hydrazones were in silico evaluated using computer program PASS as antimicrobial agents. The experimental evaluation revealed that all compounds have low to moderate ...antibacterial activity against all bacteria tested, except for
with MIC at a range of 0.37-3.00 mg/mL and MBC at 0.75-6.00 mg/mL. The most potent appeared to be compound
with MIC/MBC of 0.75/1.5 mg/mL, respectively. The evaluation of antibacterial activity against three resistant strains MRSA,
and
demonstrated superior activity of compounds against MRSA compared with ampicillin, which did not show bacteriostatic or bactericidal activities. All compounds exhibited good antifungal activity with MIC of 0.37-1.50 mg/mL and MFC of 1.50-3.00 mg/mL, but with different sensitivity against fungi tested. According to docking studies, 14-alpha demethylase inhibition may be responsible for antifungal activity. Two compounds were evaluated for their antibiofilm activity. Finally, drug-likeness and docking prediction were performed.
A series of thirteen new thiadiazole compounds were synthesized and evaluated for in vitro antifungal and antibacterial activity. All compound tested showed significant antifungal activity against ...all the micromycetes, compared to the commercial fungicide bifonazole. Differences in their activity depend on the substitution of different reactive groups. More specifically, best antifungal activity was shown for the synthetic analogue with methylpiperazine reactive group. Furthermore, it is apparent that different compounds reacted on different ways against bacteria. An effort was made to correlate the above mentioned differences in activity with lipophilicity studies. Furthermore, NMR and molecular modelling were used to obtain the main conformational features of a potent analogue, for future in silico studies.
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