Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.023
Filtrar
1.
Int J Mol Sci ; 24(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36675123

RESUMO

Ebselen is a low-molecular-weight organoselenium compound that has been broadly studied for its antioxidant, anti-inflammatory, and cytoprotective properties. These advantageous properties were initially associated with mimicking the activity of selenoprotein glutathione peroxidase, but the biomedical impact of this compound appear to be far more complex. Ebselen serves as a substrate or inhibitor with multiple protein/enzyme targets, whereas inhibition typically originates from the covalent modification of cysteine residues by opening the benzisoselenazolone ring and S-Se bond formation. The inhibition of enzymes of various classes and origins has been associated with substantial antimicrobial potential among other activities. In this contribution, we summarize the current state of the art regarding the antibacterial activity of ebselen. This activity, alone and in combination with commercial pharmaceuticals, against pathogens, including those resistant to drugs, is presented, together with the molecular mechanism behind the reactivity. The specific inactivation of thioredoxin reductase, bacterial toxins, and other resistance factors is considered to have certain therapeutic implications. Synergistic action and sensitization to common antibiotics assisted with the use of ebselen appear to be promising directions in the treatment of persistent infections.


Assuntos
Antibacterianos , Compostos Organosselênicos , Antibacterianos/farmacologia , Antioxidantes/farmacologia , Isoindóis , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/química , Azóis/farmacologia , Azóis/química
2.
Molecules ; 28(2)2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36677769

RESUMO

The risk of resistance development and adverse effects on human health and the environment has increased in the last decade. Furthermore, many antifungal agents fail to inhibit the pathogenesis of azole-resistant Aspergillus flavus. In this report, we isolated and identified azole-resistant A. flavus isolates from two sources of maize (white and yellow maize). The susceptibilities of Aspergillus flavus isolates were investigated by conventional antifungals such as Terbinfine, Fluconazole, Ketoconazole, Voricazole, Amphotericin, and Nystatin. Then zinc oxide nanoparticles associated with Chlorella vulgaris, which are synthesized by using the precipitation method, were examined against isolated fungi. The results showed that twelve species of white corn were isolated out of fifty isolates, while the number of isolates from the yellow corn source was only four. Interestingly, the following antifungals have an impact effect against azole-resistant A. flavus isolates: the inhibition zones of ketoconazole, voricazole, and terbinafine were 40 mm, 20 mm, and 12 mm, respectively, while the remaining antifungal agents have no effect. Similarly, the inhibition zones of the following antifungal agents were as follows: 41 mm for Terbinfine, 13 mm for Voricazole, and 11 mm for Ketoconazole against Aspergillus flavus that was isolated from yellow corn. The physiochemical characterization of zinc oxide nanoparticles provides evidence that ZnO-NPs associate with Chlorella vulgaris and have been fabricated by the precipitation method with a diameter of 25 nm. The zinc oxide nanoparticle was then used to isolate azole-resistant A. flavus, and the results show that ZnO-NPs have an effect on azole-resistant A. flavus isolation. The inhibition zone of zinc oxide nanoparticles against A. flavus (that was isolated from white corn) was 50 mm with an MIC of 50 mg/mL, while the inhibition zone of zinc oxide nanoparticles against Azole-resistant A. flavus isolated from yellow corn was 14 nm with an MIC of 25 mg/mL, which indicated that zinc oxide nanoparticles gave a better result against Azole-resistant A. flavus isolated from maize.


Assuntos
Chlorella vulgaris , Óxido de Zinco , Humanos , Antifúngicos/farmacologia , Aspergillus flavus , Zea mays , Óxido de Zinco/farmacologia , Azóis/farmacologia , Cetoconazol/farmacologia , Testes de Sensibilidade Microbiana
3.
Environ Pollut ; 318: 120894, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36549450

RESUMO

We selected azole pesticides products that are managed by setting maximum residue limits (MRLs) in the Republic of Korea and describe the estrogen receptor (ER) α-related negative effect to endocrine system using in vitro Organization for Economic Cooperation and Development performance-based test guideline. No azoles were found to be an ERα agonist. Conversely, three azoles (bitertanol, cafenstrole, and tebufenpyrad) were determined to be ERα antagonists. In addition, the ERα antagonistic activities of bitertanol, cafenstrole, and tebufenpyrad were not significantly perturbed in the existence of phase I (hydroxylation, dealkylation, oxidation or reduction) and phase II (conjugation). Regarding the mechanism underlying their ERα-mediated endocrine disrupting potentials, ERα proteins cannot be translocated to the nucleus by suppressing the dimerization of ERα in the cytoplasm by bitertanol, cafenstrole, and tebufenpyrad. These data indicated that azole pesticide products show the capability to interfere the ERα-related human endocrine system. Furthermore, we identified the mechanism of ERα-mediated endocrine disrupting by azole insecticide products through this study.


Assuntos
Receptor alfa de Estrogênio , Praguicidas , Humanos , Receptor alfa de Estrogênio/metabolismo , Dimerização , Azóis/toxicidade , Receptores de Estrogênio/metabolismo , Sistema Endócrino , Receptor beta de Estrogênio/metabolismo
4.
Int J Mol Sci ; 23(23)2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36498864

RESUMO

This review outlines the data of numerous studies relating to the broad-spectrum antiviral drug Triazavirin that was launched on the Russian pharmaceutical market in 2014 as an anti-influenza drug (the international non-patented name is Riamilovir). The range of antiviral activity of Triazavirin has been significantly expanded during recent years; in particular, it has been shown that Triazavirin exhibits activity against tick-borne encephalitis, Rift Valley fever, West Nile fever, and other infections of viral etiology. This drug has been approved for treatment of influenza and acute respiratory infections by the Russian Ministry of Health on the basis of comprehensive clinical trials involving over 450 patients. Triazavirin was found to be a highly effective and well-tolerated drug, allowing its over-the-counter sale. The recently published data on the use of Triazavirin in clinical practice for the treatment of patients with COVID-19 are discussed, with special attention paid to potential biological targets for this drug.


Assuntos
COVID-19 , Encefalite Transmitida por Carrapatos , Influenza Humana , Animais , Humanos , Antivirais/farmacologia , Antivirais/uso terapêutico , Influenza Humana/tratamento farmacológico , Azóis
5.
Molecules ; 27(23)2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36500546

RESUMO

The palladium-catalyzed direct arylation of azoles with (hetero)aryl halides is nowadays one of the most versatile and efficient procedures for the selective synthesis of heterobiaryls. Although this procedure is, due to its characteristics, also of great interest in the industrial field, the wide use of a reaction medium such as DMF or DMA, two polar aprotic solvents coded as dangerous according to environmental, health, safety (EHS) parameters, strongly limits its actual use. In contrast, the use of aromatic solvents as the reaction medium for direct arylations, although some of them show good EHS values, is poorly reported, probably due to their low solvent power against reagents and their potential involvement in undesired side reactions. In this paper we report an unprecedented selective C-5 arylation procedure involving anisole as an EHS green reaction solvent. In addition, the beneficial role of benzoic acid as an additive was also highlighted, a role that had never been previously described.


Assuntos
Azóis , Paládio , Catálise , Ácido Benzoico , Solventes
6.
J Am Chem Soc ; 144(50): 23115-23126, 2022 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-36490321

RESUMO

This manuscript describes a mild, functional group tolerant, and metal-free C-H carboxylation that enables direct access to azole-2-carboxylic acids, followed by amide coupling in one pot. This demonstrates a significant expansion of the accessible chemical space of azole-2-amides, compared to previously known methodologies. Key to the described reactivity is the use of silyl triflate reagents, which serve as reaction mediators in C-H deprotonation and stabilizers of (otherwise unstable) azole carboxylic acid intermediates. A diverse azole substrate scope designed via machine-learning-guided analysis demonstrates the broad utility of the sequence. Density functional theory calculations provide detailed insights into the role of silyl triflates in the reaction mechanism. Transferrable applications of the protocol are successfully established: (i) A low pressure (CO2 balloon) option for synthesizing azole-2-carboxylic acids without the need for high-pressure equipment; (ii) the use of 13CO2 for the synthesis of labeled compounds; (iii) isocyanates as alternative electrophiles for direct C-H amidation; (iv) and the use of the developed chemistry in a 24 × 12 parallel synthesis workflow with a 90% library success rate. Fundamentally, the reported protocol expands the use of heterocycle C-H functionalization from late-stage functionalization applications toward its use in library synthesis. It provides general access to densely functionalized azole-2-carboxylic acid building blocks and demonstrates their one-pot diversification.


Assuntos
Amidas , Ácidos Carboxílicos , Amidas/química , Ácidos Carboxílicos/química , Azóis , Dióxido de Carbono
7.
Molecules ; 27(21)2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36364219

RESUMO

A series of N-acyl derivatives of anabasine and cytisine were prepared, to discover novel, natural product-based medicinal agents. All synthesized compounds were tested for antimicrobial, antifungal, antiviral and analgesic activity. The most pronounced antibacterial activity was shown by the compounds with isoxazole fragments, while the adamantane derivatives showed the greatest antiviral effect. It was found that the majority of anabasine derivatives showed significant analgesic activity, reducing the pain response of animals to the irritating effect of acetic acid. The presence of a high level of antimicrobial and antiviral activity in newly synthesized compounds makes it possible to consider them promising for further study of their pharmacological properties.


Assuntos
Adamantano , Animais , Anabasina , Azóis , Piridinas , Analgésicos/farmacologia , Antibacterianos/farmacologia , Antivirais/farmacologia , Relação Estrutura-Atividade , Testes de Sensibilidade Microbiana
8.
BMJ Case Rep ; 15(11)2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36414342

RESUMO

Aspergillus osteomyelitis (AO) is a rare and often lethal opportunistic infection in predominantly immunocompromised patients. Treatment has shifted from amphotericin therapy to voriconazole monotherapy due to increased effectiveness and less toxicity. We report a case of an immunocompetent woman with vertebral osteomyelitis due to Aspergillus flavus who was successfully treated with surgery (requiring hardware implantation) and monotherapy posaconazole (following intolerance and hepatitis due to voriconazole). She remained well at follow-up post cessation of 12 months of antifungal therapy. We provide an updated literature review examining the role of azole monotherapy as the gold standard of treatment for AO.


Assuntos
Hepatite A , Osteomielite , Feminino , Humanos , Aspergillus flavus , Voriconazol/uso terapêutico , Osteomielite/tratamento farmacológico , Azóis
9.
J Org Chem ; 87(22): 15703-15712, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36331418

RESUMO

Installing a fluoroalkyl group onto the nitrogen atom of azoles represents a potential strategy for lead optimization in medicinal chemistry. Herein, we describe a method for the N-trifluoropropylation of azoles. This process is accomplished using a combination of regioselective N-vinylation and sequential hydrogenation. The two-step sequence is applicable to a diverse set of azoles and tolerates a wide range of functionalities. In addition, we showcase its practicability and utility through the gram-scale synthesis and the late-stage modification of a complex molecule.


Assuntos
Azóis , Nitrogênio , Azóis/química , Hidrogenação , Catálise
10.
Ecotoxicol Environ Saf ; 247: 114246, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36332405

RESUMO

Several pesticides widely used in agriculture have been considered to be endocrine disrupting chemicals through their binding affinities to estrogen or androgen receptors. This study was conducted to clarify the human androgen receptor (hAR)-mediated genomic endocrine disrupting mechanism of eight selected pesticide products by in vitro assay providing the Organization for Economic Co-operation and Development Test Guideline No. 458, 22Rv1/MMTV_GR-KO AR transcriptional activation assay and a homo-dimerization confirmation assay. None of the tested pesticide products showed an AR agonistic effect, whereas they were all determined to be AR antagonists at non-toxic concentrations. Also, the eight pesticide products were verified as true AR antagonists through a specificity control test. In the Bioluminescence Resonance Energy Transfer-based AR homo-dimerization confirmation assay, the eight pesticide products did not induce AR homo-dimerization. Additionally, western blotting revealed that none of the eight pesticide products induced AR translocation from the cytoplasm to the nucleus. In conclusion, we found for the first-time evidence to understand the AR-mediated endocrine disrupting mechanisms induced by selected azole and organophosphorus pesticide products.


Assuntos
Praguicidas , Receptores Androgênicos , Humanos , Receptores Androgênicos/genética , Dimerização , Compostos Organofosforados/toxicidade , Azóis , Praguicidas/toxicidade , Genômica
11.
J Antimicrob Chemother ; 77(Suppl_2): ii11-ii20, 2022 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-36426672

RESUMO

Most invasive fungal infections are opportunistic in nature but the epidemiology is constantly changing, with new risk groups being identified. Neutropenia is a classical risk factor for fungal infections, while critically ill patients in the ICU are now increasingly at risk of yeast and mould infections. Factors to be considered when choosing antifungal treatment include the emergence of rarer fungal pathogens, the risk of resistance to azoles and echinocandins and the possibility of drug-drug interactions. Liposomal amphotericin B has retained its place in the therapeutic armamentarium based on its clinical profile: a broad spectrum of antifungal activity with a low risk of resistance, predictable pharmacokinetics with a rapid accumulation at the infection site (including biofilms), a low potential for drug-drug interactions and a low risk of acute and chronic treatment-limiting toxicities versus other formulations of amphotericin B. It is a suitable choice for the first-line empirical or pre-emptive treatment of suspected fungal infections in neutropenic haematology patients and is an excellent alternative for patients with documented fungal disease who can no longer tolerate or continue their first-line azole or echinocandin therapy, both in the haematology setting and in the ICU. Moreover, it is the first-line drug of choice for the treatment of invasive mucormycosis. Finally, liposomal amphotericin B is one of the few antifungal agents approved for use in children of all ages over 1 month and is included in paediatric-specific guidelines for the management of fungal disease.


Assuntos
Anfotericina B , Antifúngicos , Infecções Fúngicas Invasivas , Humanos , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Azóis , Equinocandinas/uso terapêutico , Neutropenia/complicações , Infecções Fúngicas Invasivas/tratamento farmacológico
12.
J Antimicrob Chemother ; 77(Suppl_2): ii21-ii34, 2022 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-36426674

RESUMO

Advances in medicine have led to a growing number of people with compromised or suppressed immune systems who are susceptible to invasive fungal infections. In particular, severe fungal infections are becoming increasingly common in ICUs, affecting people within and outside of traditional risk groups alike. This is exemplified by the emergence of severe viral pneumonia as a significant risk factor for invasive pulmonary aspergillosis, and the recognition of influenza-associated pulmonary aspergillosis and, more recently, COVID-19-associated pulmonary aspergillosis. The treatment landscape for haematological malignancies has changed considerably in recent years, and some recently introduced targeted agents, such as ibrutinib, are increasing the risk of invasive fungal infections. Consideration must also be given to the risk of drug-drug interactions between mould-active azoles and small-molecule kinase inhibitors. At the same time, infections caused by rare moulds and yeasts are increasing, and diagnosis continues to be challenging. There is growing concern about azole resistance among both moulds and yeasts, mandating continuous surveillance and personalized treatment strategies. It is anticipated that the epidemiology of fungal infections will continue to change and that new populations will be at risk. Early diagnosis and appropriate treatment remain the most important predictors of survival, and broad-spectrum antifungal agents will become increasingly important. Liposomal amphotericin B will remain an essential therapeutic agent in the armamentarium needed to manage future challenges, given its broad antifungal spectrum, low level of acquired resistance and limited potential for drug-drug interactions.


Assuntos
Infecções Fúngicas Invasivas , Micoses , Aspergilose Pulmonar , Humanos , Micoses/tratamento farmacológico , Micoses/epidemiologia , Micoses/diagnóstico , Antifúngicos/uso terapêutico , Antifúngicos/farmacologia , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/epidemiologia , Azóis/uso terapêutico , Fungos , Aspergilose Pulmonar/tratamento farmacológico
13.
Nat Chem Biol ; 18(11): 1253-1262, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36229681

RESUMO

Fungal transcription factor Upc2 senses ergosterol levels and regulates sterol biosynthesis and uptake. Constitutive activation of Upc2 causes azole resistance in Candida species. We determined the structure of ergosterol-bound Upc2, revealing the ligand specificity and transcriptional regulation. Ergosterol binding involves conformational changes of the ligand-binding domain, creating a shape-complementary hydrophobic pocket. The conserved helix α12 and glycine-rich loop are critical for sterol recognition by forming the pocket wall. The mutations of the glycine-rich loop inhibit ligand binding by steric clashes and constitutively activate Upc2. The translocation of Upc2 is regulated by Hsp90 chaperone in a sterol-dependent manner. Ergosterol-bound Upc2 associates with Hsp90 using the C-terminal tail, which retains the inactive Upc2 in the cytosol. Ergosterol dissociation induces a conformational change of the C-terminal tail, releasing Upc2 from Hsp90 for nuclear transport by importin α. The understanding of the regulatory mechanism provides an antifungal target for the treatment of azole-resistant Candida infections.


Assuntos
Antifúngicos , Azóis , Azóis/farmacologia , Antifúngicos/farmacologia , Farmacorresistência Fúngica/genética , Esteróis , Ligantes , alfa Carioferinas/genética , alfa Carioferinas/metabolismo , Ergosterol/genética , Ergosterol/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Glicina/metabolismo , Proteínas Fúngicas/metabolismo , Regulação Fúngica da Expressão Gênica
14.
Int J Mol Sci ; 23(20)2022 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-36293395

RESUMO

Aspergillus species, especially A. fumigatus, and to a lesser extent others (A. flavus, A. niger, A. terreus), although rarely pathogenic to healthy humans, can be very aggressive to immunocompromised patients (they are opportunistic pathogens). Although survival rates for such infections have improved in recent decades following the introduction of azole derivatives, they remain a clinical challenge. The fact that current antifungals act as fungistatic rather than fungicide, that they have limited safety, and that resistance is becoming increasingly common make the need for new, more effective, and safer therapies to become more acute. Over the last decades, knowledge about the molecular biology of A. fumigatus and other Aspergillus species, and particularly of calcineurin, Hsp90, and their signaling pathway proteins, has progressed remarkably. Although calcineurin has attracted much interest, its adverse effects, particularly its immunosuppressive effects, make it less attractive than it might at first appear. The situation is not very different for Hsp90. Other proteins from their signaling pathways, such as protein kinases phosphorylating the four SPRR serine residues, CrzA, rcnA, pmcA-pmcC (particularly pmcC), rfeF, BAR adapter protein(s), the phkB histidine kinase, sskB MAP kinase kinase, zfpA, htfA, ctfA, SwoH (nucleoside diphosphate kinase), CchA, MidA, FKBP12, the K27 lysine position from Hsp90, PkcA, MpkA, RlmA, brlA, abaA, wetA, other heat shock proteins (Hsp70, Hsp40, Hsp12) currently appear promising and deserve further investigation as potential targets for antifungal drug development.


Assuntos
Fungicidas Industriais , Núcleosídeo-Difosfato Quinase , Humanos , Antifúngicos/farmacologia , Antifúngicos/metabolismo , Calcineurina/metabolismo , Aspergillus fumigatus/metabolismo , Proteínas de Choque Térmico/metabolismo , Lisina/metabolismo , Proteína 1A de Ligação a Tacrolimo , Fungicidas Industriais/farmacologia , Histidina Quinase/metabolismo , Azóis/farmacologia , Proteínas de Choque Térmico HSP90/metabolismo , Aspergillus/metabolismo , Núcleosídeo-Difosfato Quinase/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Serina/metabolismo , Proteínas Fúngicas/metabolismo
15.
Appl Microbiol Biotechnol ; 106(21): 7085-7097, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36184687

RESUMO

The last decade has witnessed the rise of an extremely threatening healthcare-associated multidrug-resistant non-albicans Candida (NAC) species, Candida auris. Since besides target alterations, efflux mechanisms contribute maximally to antifungal resistance, it is imperative to investigate their contributions in this pathogen. Of note, within the major facilitator superfamily (MFS) of efflux pumps, drug/H+ antiporter family 1 (DHA1) has been established as a predominant contributor towards xenobiotic efflux. Our study provides a complete landscape of DHA1 transporters encoded in the genome of C. auris. This study identifies 14 DHA1 transporters encoded in the genome of the pathogen. We also construct deletion and heterologous overexpression strains for the most important DHA1 drug transporter, viz., CauMdr1 to map the spectrum of its substrates. While the knockout strain did not show any significant changes in the resistance patterns against most of the tested substrates, the ortholog when overexpressed in a minimal background Saccharomyces cerevisiae strain, AD1-8u-, showed significant enhancement in the minimum inhibitory concentrations (MICs) against a large panel of antifungal molecules. Altogether, the present study provides a comprehensive template for investigating the role of DHA1 members of C. auris in antifungal resistance mechanisms. KEY POINTS: • Fourteen putative DHA1 transporters are encoded in the Candida auris genome. • Deletion of the CauMDR1 gene does not lead to major changes in drug resistance. • CauMdr1 recognizes and effluxes numerous xenobiotics, including prominent azoles.


Assuntos
Antifúngicos , Candida auris , Antifúngicos/farmacologia , Xenobióticos , Candida/genética , Azóis , Proteínas de Membrana Transportadoras/genética , Testes de Sensibilidade Microbiana , Saccharomyces cerevisiae/genética , Antiporters , Genômica
16.
Med Mycol ; 60(11)2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36240494

RESUMO

The yeast SKI (superkiller) complex was originally identified from cells that were infected by the M 'killer' virus. Ski2, as the core of the SKI complex, is a cytoplasmic cofactor and regulator of RNA-degrading exosome. The putative RNA helicase Ski2 was highly conserved from yeast to animals and has been demonstrated to play a key role in the regulation of RNA surveillance, temperature sensitivity, and growth in several yeasts but not yet in Cryptococcus neoformans (C. neoformans). Here, we report the identification of a gene encoding an equivalent Ski2 protein, named SKI2, in the fungal pathogen C. neoformans. To obtain insights into the function of Ski2, we created a mutant strain, ski2Δ, with the CRISPR-Cas9 editing tool. Disruption of SKI2 impaired cell wall integrity. Further investigations revealed the defects of the ski2Δ mutant in resistance to osmotic stresses and extreme growth temperatures. However, significantly, the ability to undergo invasive growth under nutrient-depleted conditions was increased in the ski2Δ mutant. More importantly, our results showed that the ski2Δ mutant exhibited slightly lower virulence and severe susceptibility to anti-ribosomal drugs by comparison to the wild type, but it developed multidrug resistance to azoles and flucytosine. By constructing the double deletion strain ski2Δafr1Δ, we verified that increased Afr1 in ski2Δ contributed to the azole resistance, which might be influenced by nonclassical small interfering RNA. Our work suggests that Ski2 plays critical roles in drug resistance and regulation of gene transcription in the yeast pathogen C. neoformans.


Assuntos
Cryptococcus neoformans , Farmacorresistência Fúngica , Proteínas Fúngicas , Azóis/farmacologia , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , RNA Helicases/metabolismo , Farmacorresistência Fúngica/genética , Estresse Fisiológico
17.
Eur Rev Med Pharmacol Sci ; 26(20): 7713-7718, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36314342

RESUMO

Antimicrobial resistance remains a worldwide issue with a major clinical and economic impact, leading to exceeding mortality, increased frequency of hospitalization and a great burden on the healthcare systems. Vulvovaginitis, especially when due to mixed infections, has emerged as a condition for which appropriate selection of antimicrobial therapy and proper antimicrobial stewardship programs (ASPs) may contribute to minimizing the resistance development. This review discusses the appropriateness of selecting treatment for vulvovaginitis in order to reduce the development of resistance in gynecological practice. Narrative review based on a selection of literature performed according to the Authors' experience and a MEDLINE search using the following keywords: "vaginitis" OR "Candida" OR "fungal infection" AND "antifungal therapy". No limits were applied, but papers were selected for inclusion in this narrative review according to their relevance to the topic, as judged by the Authors. Worldwide, antimicrobial treatment in gynecology and ASPs focuses on prescribing systemic and expensive antifungal drugs, while treatment selection should consider several factors. Recently, topical azoles have been recommended as suitable alternatives to oral systemic azoles, given their similar efficacy in limiting clinical recurrence. In particular, fenticonazole has already been proposed as an alternative to systemic antifungal drugs to limit the onset of resistance. Optimizing the selection of antimicrobial treatment can help reduce the development of resistance in gynecological practice. Given its wide action spectrum and ability to exert antimicrobial activity against fungi, bacteria and mixed infections, fenticonazole may be considered a suitable first-line, empiric therapy for vaginal and mixed infections, avoiding alteration of intestinal microflora and minimizing the risk of selection of drug-resistant microbial strains.


Assuntos
Anti-Infecciosos , Coinfecção , Vulvovaginite , Feminino , Humanos , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Vulvovaginite/tratamento farmacológico , Azóis , Antibacterianos/uso terapêutico
18.
Biomed Res Int ; 2022: 6722245, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36277891

RESUMO

Mucormycosis is one among the life-threatening fungal infections with high morbidity and mortality. It is an uncommon and rare infection targeting people with altered immunity. This lethal infection induced by fungi belonging to the Mucorales family is very progressive in nature. The incidence has increased in recent decades owing to the rise in immunocompromised patients. Disease management involves a multimodal strategy including early administration of drugs and surgical removal of infected tissues. Among the antifungals, azoles and amphotericin B remain the gold standard drugs of choice for initial treatment. The order Mucorales are developing a high level of resistance to the available systemic antifungal drugs, and the efficacy still remains below par. Deciphering the molecular mechanisms behind the antifungal resistance in Mucormycosis would add vital information to our available antifungal armamentarium and design novel therapies. Therefore, in this review, we have discussed the mechanisms behind Mucormycosis antifungal resistance. Moreover, this review also highlights the basic mechanisms of action of antifungal drugs and the resistance landscape which is expected to augment future treatment strategies.


Assuntos
Mucorales , Mucormicose , Humanos , Mucormicose/tratamento farmacológico , Mucormicose/microbiologia , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Anfotericina B/farmacologia , Anfotericina B/uso terapêutico , Mucorales/genética , Azóis/uso terapêutico
19.
Commun Biol ; 5(1): 1118, 2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36271293

RESUMO

The increasing prevalence of candidosis caused by Candida glabrata is related to its ability to acquire azole resistance. Although azole resistance mechanisms are well known, the mechanisms for azole import into fungal cells have remained obscure. In this work, we have characterized two hexose transporters in C. glabrata and further investigate their role as potential azole importers. Three azole susceptible C. glabrata clinical isolates were evolved towards azole resistance and the acquired resistance phenotype was found to be independent of CgPDR1 or CgERG11 mutations. Through whole-genome sequencing, CgHXT4/6/7 was found to be mutated in the three evolved strains, when compared to their susceptible parents. CgHxt4/6/7 and the 96% identical CgHxt6/7 were found to confer azole susceptibility and increase azole accumulation in C. glabrata cells, strikingly rescuing the susceptibility phenotype imposed by CgPDR1 deletion, while the identified loss-of-function mutation in CgHXT4/6/7, leads to increased azole resistance. In silico docking analysis shows that azoles display a strong predicted affinity for the glucose binding site of CgHxt4/6/7. Altogether, we hypothesize that hexose transporters, such as CgHxt4/6/7 and CgHxt6/7, may constitute a family of azole importers, involved in clinical drug resistance in fungal pathogens, and constituting promising targets for improved antifungal therapy.


Assuntos
Azóis , Candida glabrata , Candida glabrata/genética , Azóis/farmacologia , Azóis/uso terapêutico , Farmacorresistência Fúngica/genética , Antifúngicos/farmacologia , Glucose , Evolução Molecular , Hexoses
20.
PLoS Pathog ; 18(10): e1010860, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36264855

RESUMO

Global banana production is currently challenged by Panama disease, caused by Fusarium oxysporum f.sp. cubense Tropical Race 4 (FocTR4). There are no effective fungicide-based strategies to control this soil-borne pathogen. This could be due to insensitivity of the pathogen to fungicides and/or soil application per se. Here, we test the effect of 12 single-site and 9 multi-site fungicides against FocTR4 and Foc Race1 (FocR1) in quantitative colony growth, and cell survival assays in purified FocTR4 macroconidia, microconidia and chlamydospores. We demonstrate that these FocTR4 morphotypes all cause Panama disease in bananas. These experiments reveal innate resistance of FocTR4 to all single-site fungicides, with neither azoles, nor succinate dehydrogenase inhibitors (SDHIs), strobilurins or benzimidazoles killing these spore forms. We show in fungicide-treated hyphae that this innate resistance occurs in a subpopulation of "persister" cells and is not genetically inherited. FocTR4 persisters respond to 3 µg ml-1 azoles or 1000 µg ml-1 strobilurins or SDHIs by strong up-regulation of genes encoding target enzymes (up to 660-fold), genes for putative efflux pumps and transporters (up to 230-fold) and xenobiotic detoxification enzymes (up to 200-fold). Comparison of gene expression in FocTR4 and Zymoseptoria tritici, grown under identical conditions, reveals that this response is only observed in FocTR4. In contrast, FocTR4 shows little innate resistance to most multi-site fungicides. However, quantitative virulence assays, in soil-grown bananas, reveals that only captan (20 µg ml-1) and all lipophilic cations (200 µg ml-1) suppress Panama disease effectively. These fungicides could help protect bananas from future yield losses by FocTR4.


Assuntos
Fungicidas Industriais , Fusarium , Musa , Fungicidas Industriais/farmacologia , Succinato Desidrogenase , Estrobilurinas , Captana , Xenobióticos , Doenças das Plantas/genética , Esporos Fúngicos , Solo , Azóis , Benzimidazóis
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...