The opportunistic pathogen Candida parapsilosis is a major causative agent of candidiasis leading to death in immunocompromised individuals. Azoles are the first line of defense in their treatment. The purpose of this study was to characterize eight fluconazole-resistant and sensitive C. parapsilosis hospital isolates through a battery of phenotypic tests that target pathogenicity attributes such as virulence, biofilm formation, stress resistance, and ergosterol content. Whole genome sequencing was carried out to identify mutations in key pathogenicity and resistance genes. Phylogenetic comparison was performed to determine strain relatedness and clonality. Genomic data and phylogenetic analysis revealed that two isolates were C. orthopsilosis and C. metapsilosis misidentified as C. parapsilosis. Whole genome sequencing analysis revealed known and novel mutations in key drug resistance and pathogenicity genes such as ALS6, ALS7, SAPP3, SAP7, SAP9, CDR1, ERG6, ERG11 and UPC2. Phylogenetic analysis revealed a high degree of relatedness and clonality within our C. parapsilosis isolates. Our results showed that resistant isolates exhibited an increase in biofilm content compared to the sensitive isolates. In conclusion, our study is the first of its kind in Lebanon to describe phenotypic and genotypic characteristics of nosocomial C. parapsilosis complex isolates having a remarkable ability to form biofilms.
- Klíčová slova
- Candida parapsilosis, Biofilm, Clonality, Fluconazole, Pathogenicity, Resistance,
- MeSH
- antifungální látky * farmakologie MeSH
- biofilmy * růst a vývoj MeSH
- Candida parapsilosis * genetika izolace a purifikace klasifikace MeSH
- fenotyp * MeSH
- flukonazol farmakologie MeSH
- fungální léková rezistence * genetika MeSH
- fylogeneze * MeSH
- genotyp * MeSH
- infekce spojené se zdravotní péčí mikrobiologie MeSH
- kandidóza * mikrobiologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti * MeSH
- nemocnice MeSH
- sekvenování celého genomu * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Libanon MeSH
- Názvy látek
- antifungální látky * MeSH
- flukonazol MeSH
Amphotericin B (AmB) is one of the most effective antifungal drugs, with a strong, dose-dependent activity against most Candida and Aspergillus species responsible for life-threatening infections. However, AmB is severely toxic, which hinders its broad use. In this proof-of-concept study, we demonstrate that prodrugging AmB considerably decreases AmB toxicity without affecting its fungicidal activity. For this purpose, we modified the AmB structure by attaching a designer phosphate promoiety, thereby switching off its mode of action and preventing its toxic effects. The original fungicidal activity of AmB was then restored upon prodrug activation by host plasma enzymes. These AmB prodrugs showed a safer toxicity profile than commercial AmB deoxycholate in Candida and Aspergillus species and significantly prolonged larval survival of infected Galleria mellonella larvae. Based on these findings, prodrugging toxic antifungals may be a viable strategy for broadening the antifungal arsenal, opening up opportunities for targeted prodrug design.
- Klíčová slova
- Amphotericin, Antifungal, Aspergillus fumigatus, Candida albicans, Fungal infection, Galleria mellonella, Prodrugs, Toxicity,
- MeSH
- amfotericin B * farmakologie MeSH
- antifungální látky * farmakologie chemie chemická syntéza MeSH
- Aspergillus účinky léků MeSH
- Candida účinky léků MeSH
- larva účinky léků MeSH
- mikrobiální testy citlivosti * MeSH
- molekulární struktura MeSH
- můry účinky léků MeSH
- prekurzory léčiv * farmakologie chemie chemická syntéza MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- amfotericin B * MeSH
- antifungální látky * MeSH
- prekurzory léčiv * MeSH
Infectious diseases, including bacterial, fungal, and viral, have once again gained urgency in the drug development pipeline after the recent COVID-19 pandemic. Tuberculosis (TB) is an old infectious disease for which eradication has not yet been successful. Novel agents are required to have potential activity against both drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of TB. In this study, we present a series of 2-phenyl-N-(pyridin-2-yl)acetamides in an attempt to investigate their possible antimycobacterial activity, cytotoxicity on the HepG2 liver cancer cell line, and-as complementary testing-their antibacterial and antifungal properties against a panel of clinically important pathogens. This screening resulted in one compound with promising antimycobacterial activity-compound 12, MICMtb H37Ra = 15.625 μg/mL (56.26 μM). Compounds 17, 24, and 26 were further screened for their antiproliferative activity against human epithelial kidney cancer cell line A498, human prostate cancer cell line PC-3, and human glioblastoma cell line U-87MG, where they were found to possess interesting activity worth further exploration in the future.
- Klíčová slova
- antibacterial, antimycobacterial, antiproliferative, drug design, pyridine, tuberculosis,
- MeSH
- acetamidy * chemie farmakologie MeSH
- antifungální látky farmakologie chemie chemická syntéza MeSH
- antituberkulotika farmakologie chemie MeSH
- antitumorózní látky farmakologie chemie MeSH
- buňky Hep G2 MeSH
- lidé MeSH
- mikrobiální testy citlivosti * MeSH
- Mycobacterium tuberculosis * účinky léků MeSH
- nádorové buněčné linie MeSH
- proliferace buněk * účinky léků MeSH
- pyridiny chemie farmakologie MeSH
- SARS-CoV-2 účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- acetamidy * MeSH
- antifungální látky MeSH
- antituberkulotika MeSH
- antitumorózní látky MeSH
- pyridiny MeSH
Cryptococcosis is an invasive mycosis caused mainly by Cryptococcus gattii and C. neoformans and is treated with amphotericin B (AMB), fluconazole and 5-fluorocytosine. However, antifungal resistance, limited and toxic antifungal arsenal stimulate the search for therapeutic strategies such as drug repurposing. Among the repurposed drugs studied, the selective serotonin reuptake inhibitors (SSRIs) have shown activity against Cryptococcus spp. However, little is known about the antifungal effect of duloxetine hydrochloride (DH), a selective serotonin and norepinephrine reuptake inhibitor (SSNRI), against C. neoformans and C. gattii. In this study, DH inhibited the growth of several C. neoformans and C. gattii strains at concentrations ranging from 15.62 to 62.50 µg/mL. In addition, DH exhibited fungicidal activity ranging from 15.62 to 250 µg/mL. In biofilm, DH treatment reduced Cryptococcus spp. biomass at a level comparable to AMB, with a significant reduction (85%) for C. neoformans biofilms. The metabolic activity of C. neoformans and C. gattii biofilms decreased significantly (99%) after treatment with DH. Scanning electron micrographs confirmed the anti-biofilm activity of DH, as isolated cells could be observed after treatment. In conclusion, DH showed promising antifungal activity against planktonic cells and biofilms of C. neoformans and C. gattii, opening perspectives for further studies with DH in vivo.
- Klíčová slova
- Cryptococcus spp, Biofilm, Drug repurposing, Duloxetine hydrochloride,
- MeSH
- antifungální látky * farmakologie MeSH
- biofilmy * účinky léků MeSH
- Cryptococcus gattii * účinky léků MeSH
- Cryptococcus neoformans * účinky léků růst a vývoj MeSH
- duloxetinum hydrochlorid * farmakologie MeSH
- kryptokokóza farmakoterapie mikrobiologie MeSH
- mikrobiální testy citlivosti * MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antifungální látky * MeSH
- duloxetinum hydrochlorid * MeSH
The association of silver nanoparticles (AgNps) to sealant agent Palaseal® can be a promising alternative for complete denture wearers who may develop denture stomatitis (DS). The study aimed to evaluate the anti-Candida and biocompatible potential of silver nanoparticles synthesized by three routes associated with denture glaze to prevent and/or treat oral candidiasis. Surface acrylic resin specimens were treated with different associations of glaze with AgNps (VER+AgUV, VER+AgTurk and VER+AgGm). As controls, specimens were treated with glaze+nystatin (VER+Nyst), glaze only (VER) or submerged in PBS (PBS). Afterwards, Candida albicans biofilm was developed for 24 h, 15 d and 30 d. Subsequently, the biofilm was quantified by CFU/mL, XTT assay and confocal laser scanning microscopy. Fibroblasts were submitted to conditioned medium with the same associations for 24, 48 and 72 h and LIVE/DEAD® viability test was carried out. Regardless of the period, there was a significant reduction (p < 0.01) of viable fungal cells load, as well as inhibition of fungal metabolic activity, in specimens treated with glaze+AgNps associations, compared to VER and PBS. The anti-Candida effects of the associations were similar to the VER+Nyst group, with emphasis on VER+AgGm, which showed the highest percentage values of non-viable fungal cells maintained over time. The associations did not prove toxicity to fibroblasts. The AgNps exerted antimicrobial activity against C. albicans biofilms and are biocompatible. The most effective results were achieved with the association of glaze+silver nanoparticles synthesized by the green chemistry method (AgGm), proving to be an innovative alternative in the management of DS.
- Klíčová slova
- Candida albicans, Silver nanoparticles, Stomatitis under denture, Surface sealant agent,
- MeSH
- antifungální látky * farmakologie chemie MeSH
- biofilmy * účinky léků MeSH
- Candida albicans * účinky léků MeSH
- fibroblasty účinky léků MeSH
- kovové nanočástice * chemie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- orální kandidóza farmakoterapie mikrobiologie MeSH
- stomatitida vyvolaná protézou * mikrobiologie farmakoterapie MeSH
- stříbro * farmakologie chemie MeSH
- zubní náhrady mikrobiologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antifungální látky * MeSH
- stříbro * MeSH
The current global scenario presents us with a growing increase in infections caused by fungi, referred to by specialists in the field as a "silent epidemic", aggravated by the limited pharmacological arsenal and increasing resistance to this therapy. For this reason, drug repositioning and therapeutic compound combinations are promising strategies to mitigate this serious problem. In this context, this study investigates the antifungal activity of the non-toxic, low-cost and widely available cationic polyelectrolyte Poly(diallyldimethylammonium chloride) (PDDA), in combination with different antifungal drugs: systemic (amphotericin B, AMB), topical (clioquinol, CLIO) and oral (nitroxoline, NTX). For each combination, different drug:PDDA ratios were tested and, through the broth microdilution technique, the minimum inhibitory concentration (MIC) of these drugs in the different ratios against clinically important Candida species strains was determined. Overall, PDDA combinations with the studied drugs demonstrated a significant increase in drug activity against most strains, reaching MIC reductions of up to 512 fold for the fluconazole resistant Candida krusei (Pichia kudriavzevii). In particular, the AMB-PDDA combination 1:99 was highly effective against AMB-resistant strains, demonstrating the excellent profile of PDDA as an adjuvant/association in novel antifungal formulations with outdated conventional drugs.
- MeSH
- amfotericin B farmakologie MeSH
- antifungální látky * farmakologie MeSH
- Candida * účinky léků MeSH
- fungální léková rezistence MeSH
- kandidóza mikrobiologie farmakoterapie MeSH
- kvartérní amoniové sloučeniny * farmakologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti * MeSH
- Pichia MeSH
- polyelektrolyty farmakologie MeSH
- polyethyleny farmakologie chemie MeSH
- synergismus léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- amfotericin B MeSH
- antifungální látky * MeSH
- kvartérní amoniové sloučeniny * MeSH
- poly-N,N-dimethyl-N,N-diallylammonium chloride MeSH Prohlížeč
- polyelektrolyty MeSH
- polyethyleny MeSH
Since the discovery of antimicrobial agents, the misuse of antibiotics has led to the emergence of bacterial strains resistant to both antibiotics and common disinfectants like quaternary ammonium compounds (QACs). A new class, 'gemini' QACs, which contain two polar heads, has shown promise. Octenidine (OCT), a representative of this group, is effective against resistant microorganisms but has limitations such as low solubility and high cytotoxicity. In this study, we developed 16 novel OCT derivatives. These compounds were subjected to in silico screening to predict their membrane permeation. Testing against nosocomial bacterial strains (G+ and G-) and their biofilms revealed that most compounds were highly effective against G+ bacteria, while compounds 7, 8, and 10-12 were effective against G- bacteria. Notably, compounds 6-8 were significantly more effective than OCT and BAC standards across the bacterial panel. Compound 12 stood out due to its low cytotoxicity and broad-spectrum antimicrobial activity, comparable to OCT. It also demonstrated impressive antifungal activity. Compound 1 was highly selective to fungi and four times more effective than OCT without its cytotoxicity. Several compounds, including 4, 6, 8, 9, 10, and 12, showed strong virucidal activity against murine cytomegalovirus and herpes simplex virus 1. In conclusion, these gemini QACs, especially compound 12, offer a promising alternative to current disinfectants, addressing emerging resistances with their enhanced antimicrobial, antifungal, and virucidal properties.
- Klíčová slova
- Disinfection, Octenidine, Quaternary ammonium salts, Resistance, Synthesis,
- MeSH
- antibakteriální látky * farmakologie chemická syntéza chemie MeSH
- antifungální látky farmakologie chemická syntéza chemie MeSH
- antivirové látky farmakologie chemická syntéza chemie MeSH
- Bacteria účinky léků MeSH
- biofilmy účinky léků MeSH
- houby účinky léků MeSH
- iminy MeSH
- kvartérní amoniové sloučeniny * farmakologie chemická syntéza chemie MeSH
- lidé MeSH
- mikrobiální testy citlivosti * MeSH
- molekulární struktura MeSH
- myši MeSH
- pyridinové sloučeniny farmakologie chemická syntéza chemie MeSH
- pyridiny farmakologie chemie chemická syntéza MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antibakteriální látky * MeSH
- antifungální látky MeSH
- antivirové látky MeSH
- iminy MeSH
- kvartérní amoniové sloučeniny * MeSH
- octenidine MeSH Prohlížeč
- pyridinové sloučeniny MeSH
- pyridiny MeSH
Candida auris has drawn global attention due to its alarming multidrug resistance and the emergence of pan resistant strains. C. auris poses a significant risk in nosocomial candidemia especially among immunocompromised patients. C. auris showed unique virulence characteristics associated with cell wall including cell polymorphism, adaptation, endurance on inanimate surfaces, tolerance to external conditions, and immune evasion. Notably, it possesses a distinctive cell wall composition, with an outer mannan layer shielding the inner 1,3-β glucan from immune recognition, thereby enabling immune evasion and drug resistance. This review aimed to comprehend the association between unique characteristics of C. auris's cell wall and virulence, resistance mechanisms, and immune evasion. This is particularly relevant since the fungal cell wall has no human homology, providing a potential therapeutic target. Understanding the complex interactions between the cell wall and the host immune system is essential for devising effective treatment strategies, such as the use of repurposed medications, novel therapeutic agents, and immunotherapy like monoclonal antibodies. This therapeutic targeting strategy of C. auris holds promise for effective eradication of this resilient pathogen.
- Klíčová slova
- Candida auris, Cell wall, Complexity, Immune evasion, Resistance, Treatment,
- MeSH
- antifungální látky * terapeutické užití farmakologie MeSH
- beta-glukany metabolismus MeSH
- buněčná stěna * MeSH
- Candida auris * patogenita MeSH
- fungální léková rezistence MeSH
- imunitní únik * MeSH
- kandidóza mikrobiologie imunologie farmakoterapie MeSH
- lidé MeSH
- morfogeneze MeSH
- virulence MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- antifungální látky * MeSH
- beta-1,3-glucan MeSH Prohlížeč
- beta-glukany MeSH
A chemical investigation of Laburnicola nematophila, isolated from cysts of the plant parasitic nematode Heterodera filipjevi, affored three dactylfungin derivatives (1-3) and three tetralone congeners (4-6). Dactylfungin C (1), laburnicolin (4), and laburnicolenone (5) are previously undescribed natural products. Chemical structures of the isolated compounds were determined based on 1D and 2D NMR spectroscopic analyses together with HR-ESI-MS spectrometry and comparison with data reported in the literature. The relative configurations of compounds 1, 2, and 4-6 were determined based on their ROESY data and analysis of their coupling constants (J values). The absolute configurations of 4-6 were determined through the comparison of their measured and calculated TDDFT-ECD spectra. Compounds 1-3 were active against azole-resistant Aspergillus fumigatus.
- MeSH
- antifungální látky farmakologie chemie MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- tetralony * farmakologie chemie MeSH
- Tylenchoidea účinky léků MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antifungální látky MeSH
- tetralony * MeSH
BACKGROUND: The prevalence of Candida glabrata healthcare-associated infections is on the rise worldwide and in Lebanon, Candida glabrata infections are difficult to treat as a result of their resistance to azole antifungals and their ability to form biofilms. OBJECTIVES: The first objective of this study was to quantify biofilm biomass in the most virulent C. glabrata isolates detected in a Lebanese hospital. In addition, other pathogenicity attributes were evaluated. The second objective was to identify the mechanisms of azole resistance in those isolates. METHODS: A mouse model of disseminated systemic infection was developed to evaluate the degree of virulence of 41 azole-resistant C. glabrata collected from a Lebanese hospital. The most virulent isolates were further evaluated alongside an isolate having attenuated virulence and a reference strain for comparative purposes. A DNA-sequencing approach was adopted to detect single nucleotide polymorphisms (SNPs) leading to amino acid changes in proteins involved in azole resistance and biofilm formation. This genomic approach was supported by several phenotypic assays. RESULTS: All chosen virulent isolates exhibited increased adhesion and biofilm biomass compared to the isolate having attenuated virulence. The amino acid substitutions D679E and I739N detected in the subtelomeric silencer Sir3 are potentially involved- in increased adhesion. In all isolates, amino acid substitutions were detected in the ATP-binding cassette transporters Cdr1 and Pdh1 and their transcriptional regulator Pdr1. CONCLUSIONS: In summary, increased adhesion led to stable biofilm formation since mutated Sir3 could de-repress adhesins, while decreased azole susceptibility could result from mutations in Cdr1, Pdh1 and Pdr1.
- Klíčová slova
- Candida glabrata, adhesion, azoles, biofilm, resistance, sequencing,
- MeSH
- antifungální látky * farmakologie MeSH
- azoly farmakologie MeSH
- biofilmy * růst a vývoj MeSH
- Candida glabrata * genetika účinky léků izolace a purifikace patogenita fyziologie MeSH
- fungální léková rezistence * genetika MeSH
- fungální proteiny genetika MeSH
- jednonukleotidový polymorfismus MeSH
- kandidóza * mikrobiologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- modely nemocí na zvířatech MeSH
- mutace * MeSH
- myši MeSH
- nemocnice MeSH
- virulence genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Libanon MeSH
- Názvy látek
- antifungální látky * MeSH
- azoly MeSH
- fungální proteiny MeSH
