Synergistic Anticandidal Activity of Etomidate and Azoles Against Clinical Fluconazole-Resistant<i>Candida</i>Isolates

Sá, Lívia Gurgel do Amaral Valente; Silva, Cecília Rocha da; Campos, Rosana de Sousa; Neto, João Batista de Andrade; Sampaio, Letícia Serpa; Nascimento, Francisca Bruna Stefany Aires do; Barroso, Fátima Dd; Silva, Lisandra J da; Queiroz, Helaine A; Cândido, Thiago M; Rodrigues, Daniel S; Leitão, Amanda C; Moraes, Manoel Odoríco de; Cavalcanti, Bruno C.; Júnior, Hélio Vn

doi:10.2217/fmb-2019-0075

Cited by 10 publications

(8 citation statements)

References 44 publications

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“…Similar to amobarbital, ABP-700 does not have any study related with any other pharmacological property. Etomidate is a very similar drug to ABP-700 and also used as sedative and hypnotic, had been previously probed to be antifungal [43] and recently repurposed as a possible influenza inhibitor considering its gene expression signature [44].…”

Section: Discussionmentioning

confidence: 99%

Drugs Repurposing Using QSAR, Docking and Molecular Dynamics for Possible Inhibitors of the SARS-CoV-2 Mpro Protease

et al. 2020

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Wuhan, China was the epicenter of the first zoonotic transmission of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) in December 2019 and it is the causative agent of the novel human coronavirus disease 2019 (COVID-19). Almost from the beginning of the COVID-19 outbreak several attempts were made to predict possible drugs capable of inhibiting the virus replication. In the present work a drug repurposing study is performed to identify potential SARS-CoV-2 protease inhibitors. We created a Quantitative Structure–Activity Relationship (QSAR) model based on a machine learning strategy using hundreds of inhibitor molecules of the main protease (Mpro) of the SARS-CoV coronavirus. The QSAR model was used for virtual screening of a large list of drugs from the DrugBank database. The best 20 candidates were then evaluated in-silico against the Mpro of SARS-CoV-2 by using docking and molecular dynamics analyses. Docking was done by using the Gold software, and the free energies of binding were predicted with the MM-PBSA method as implemented in AMBER. Our results indicate that levothyroxine, amobarbital and ABP-700 are the best potential inhibitors of the SARS-CoV-2 virus through their binding to the Mpro enzyme. Five other compounds showed also a negative but small free energy of binding: nikethamide, nifurtimox, rebimastat, apomine and rebastinib.

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Section: Discussionmentioning

confidence: 99%

Drugs Repurposing Using QSAR, Docking and Molecular Dynamics for Possible Inhibitors of the SARS-CoV-2 Mpro Protease

et al. 2020

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“…Thus, three combinations of fluconazole-resistant C. albicans and MRSA were tested. In total, 100 µl of fungal inoculum and 100 µl of bacterial inoculum to each strain association were added in a 96-well polystyrene microplate, in a 1 : 1 ratio, with incubation at 35 °C for 48 h. After this period, the wells were washed with 0.85 % saline solution, with subsequent addition of 200 µl of etomidate dilutions, corresponding to 250, 500, 1000 and 2000 µg ml −1 , and incubated at 35 °C for 24 h. These concentrations were used considering the MICs observed in the studies of Do Av Sá et al [14,16], which corresponded to 62.5 µg ml −1 for C. albicans 1 and 2, 31.2 µg ml −1 for C. albicans 3 and 1000 µg ml −1 for the three MRSA isolates. Thus, the concentrations tested were based on the highest MICs considering the combined strains.…”

Section: In Vitro Assays On Mature Mixed Biofilms Of Fluconazole-resi...mentioning

confidence: 99%

“…Etomidate has reported activity against biofilms of fluconazole-resistant C. albicans [14,15] and MRSA [16]. However, there is no description of its activity against polymicrobial biofilms.…”

Section: Introductionmentioning

confidence: 99%

Promising activity of etomidate against mixed biofilms of fluconazole-resistant Candida albicans and methicillin-resistant Staphylococcus aureus

da Silva,

Rebouças,

Cabral

et al. 2024

Journal of Medical Microbiology

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Introduction. Candida albicans and Staphylococcus aureus are recognized for their development of resistance and biofilm formation. New therapeutic alternatives are necessary in this context. Hypothesis. Etomidate shows potential application in catheters against mixed biofilms of fluconazole-resistant C. albicans and methicillin-resistant S. aureus (MRSA). Aim. The present study aimed to evaluate the activity of etomidate against mixed biofilms of fluconazole-resistant C. albicans and MRSA. Methodology. The action of etomidate against mature biofilms was verified through the evaluation of biomass and cell viability, and its ability to prevent biofilm formation in peripheral venous catheters was determined based on counts of colony forming units (c.f.u.) and confirmed by morphological analysis through scanning electron microscopy (SEM). Results. Etomidate generated a reduction (P<0.05) in biomass and cell viability starting from a concentration of 250 µg ml−1. In addition, it showed significant ability to prevent the formation of mixed biofilms in a peripheral venous catheter, as shown by a reduction in c.f.u. SEM revealed that treatment with etomidate caused substantial damage to the fungal cells. Conclusion. The results showed the potential of etomidate against polymicrobial biofilms of fluconazole-resistant C. albicans and MRSA.

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“…VANCO (4 µg ml −1 ) was used as a death control and BHI culture medium was used as a negative control for the test. The treated cells were incubated at 35 °C for 24 h [15,39,40]. Subsequently, flow cytometry and fluorescence microscopy assays were performed to evaluate the mechanism of action.…”

Section: Analysis Of the Mechanism Of Action Preparation Of Suspensio...mentioning

confidence: 99%

“…Drug repositioning has emerged as an alternative approach to identify new treatments for diseases that lack effective treatments [14]. This strategy is based on finding new therapeutic indications for existing drugs, optimizing development time and reducing costs [14,15]. An additional possibility is to use the strategy of combining non-antibiotic drugs with antibiotics in order to increase the effectiveness of treatment and reduce the risk of emergence of antimicrobial resistance [16].…”

Section: Introductionmentioning

confidence: 99%

Antibacterial activity of menadione alone and in combination with oxacillin against methicillin-resistant Staphylococcus aureus and its impact on biofilms

Leitão,

Ferreira,

Gurgel do Amaral Valente Sá

et al. 2023

Journal of Medical Microbiology

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Introduction. Antibiotic resistance is a major threat to public health, particularly with methicillin-resistant Staphylococcus aureus (MRSA) being a leading cause of antimicrobial resistance. To combat this problem, drug repurposing offers a promising solution for the discovery of new antibacterial agents. Hypothesis. Menadione exhibits antibacterial activity against methicillin-sensitive and methicillin-resistant S. aureus strains, both alone and in combination with oxacillin. Its primary mechanism of action involves inducing oxidative stress. Methodology. Sensitivity assays were performed using broth microdilution. The interaction between menadione, oxacillin, and antioxidants was assessed using checkerboard technique. Mechanism of action was evaluated using flow cytometry, fluorescence microscopy, and in silico analysis. Aim. The aim of this study was to evaluate the in vitro antibacterial potential of menadione against planktonic and biofilm forms of methicillin-sensitive and resistant S. aureus strains. It also examined its role as a modulator of oxacillin activity and investigated the mechanism of action involved in its activity. Results. Menadione showed antibacterial activity against planktonic cells at concentrations ranging from 2 to 32 µg ml−1, with bacteriostatic action. When combined with oxacillin, it exhibited an additive and synergistic effect against the tested strains. Menadione also demonstrated antibiofilm activity at subinhibitory concentrations and effectively combated biofilms with reduced sensitivity to oxacillin alone. Its mechanism of action involves the production of reactive oxygen species (ROS) and DNA damage. It also showed interactions with important targets, such as DNA gyrase and dehydroesqualene synthase. The presence of ascorbic acid reversed its effects. Conclusion. Menadione exhibited antibacterial and antibiofilm activity against MRSA strains, suggesting its potential as an adjunct in the treatment of S. aureus infections. The main mechanism of action involves the production of ROS, which subsequently leads to DNA damage. Additionally, the activity of menadione can be complemented by its interaction with important virulence targets.

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Synergistic Anticandidal Activity of Etomidate and Azoles Against Clinical Fluconazole-ResistantCandidaIsolates

Cited by 10 publications

References 44 publications

Drugs Repurposing Using QSAR, Docking and Molecular Dynamics for Possible Inhibitors of the SARS-CoV-2 Mpro Protease

Drugs Repurposing Using QSAR, Docking and Molecular Dynamics for Possible Inhibitors of the SARS-CoV-2 Mpro Protease

Promising activity of etomidate against mixed biofilms of fluconazole-resistant Candida albicans and methicillin-resistant Staphylococcus aureus

Antibacterial activity of menadione alone and in combination with oxacillin against methicillin-resistant Staphylococcus aureus and its impact on biofilms

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