OUP accepted manuscript

Katragkou, Aspasia; McCarthy, Matthew W; Meletiadis, Joseph; Hussain, Kaiser; Moradi, Patriss W.; Strauss, Gittel E.; Myint, Kyaw L; Zaw, Myo; Kovanda, Laura; Petraitienė, Rūta; Roilides, Emmanuel; Walsh, Thomas J.; Petraitis, Vidmantas

doi:10.1093/mmy/myx006

Cited by 17 publications

(4 citation statements)

References 45 publications

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“…Many studies have focused on synergistic effects as an alternative to the antifungal agents developed against Candida spp. [52][53][54][55][56][57]. However, there is a range of protocols with different interpretations [37,[58][59][60][61][62].…”

Section: Discussionmentioning

confidence: 99%

Promising antifungal activity of new oxadiazole against Candida krusei

et al. 2020

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Candida krusei is one of the most common agents of invasive candidiasis and candidemia worldwide, leading to high morbidity and mortality rates. This species has become a problem due to its intrinsic resistance and reduced susceptibility to azoles and polyenes. Moreover, the number of antifungal drugs available for candidiasis treatment is limited, demonstrating the urgent need for the discovery of novel alternative therapies. In this work, the in vivo and in vitro activities of a new oxadiazole (LMM11) were evaluated against C. krusei. The minimum inhibitory concentration ranged from 32 to 64 μg/mL with a significant reduction in the colony forming unit (CFU) count (~3 log 10). LMM11 showed fungicidal effect, similar to amphotericin, reducing the viable cell number (>99.9%) in the time-kill curve. Yeast cells presented morphological alterations and inactive metabolism when treated with LMM11. This compound was also effective in decreasing C. krusei replication inside and outside macrophages. A synergistic effect between fluconazole and LMM11 was observed. In vivo treatment with the new oxadiazole led to a significant reduction in CFU (0.85 log 10). Furthermore, histopathological analysis of the treated group exhibited a reduction in the inflammatory area. Taken together, these results indicate that LMM11 is a promising candidate for the development of a new antifungal agent for the treatment of infections caused by resistant Candida species such as C. krusei.

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Section: Discussionmentioning

confidence: 99%

Promising antifungal activity of new oxadiazole against Candida krusei

et al. 2020

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“…Reading can be performed either visually or spectrophotometrically. Nevertheless, for a more objective MIC determination and possible automation, the spectrophotometric method should be preferred [7,12]. After reading of the microplates, the quantitative data can be analyzed in different ways.…”

Section: Liquid Microdilution Technique: Checkerboardmentioning

confidence: 99%

“…This method has been used to evaluate antifungal combinations or combinations of antifungals with non-antifungal drugs against Candida spp. [12,38,39,41,46,47,49,, Cryptococcus spp. [42,59,68,70,83], and Aspergillus spp.…”

Section: Time-kill Curvesmentioning

confidence: 99%

Techniques for the Assessment of In Vitro and In Vivo Antifungal Combinations

Bidaud¹,

Schwarz

Herbreteau

et al. 2021

JoF

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Systemic fungal infections are associated with high mortality rates despite adequate treatment. Moreover, acquired resistance to antifungals is increasing, which further complicates the therapeutic management. One strategy to overcome antifungal resistance is to use antifungal combinations. In vitro, several techniques are used to assess drug interactions, such as the broth microdilution checkerboard, agar-diffusion methods, and time-kill curves. Currently, the most widely used technique is the checkerboard method. The aim of all these techniques is to determine if the interaction between antifungal agents is synergistic, indifferent, or antagonistic. However, the interpretation of the results remains difficult. Several methods of analysis can be used, based on different theories. The most commonly used method is the calculation of the fractional inhibitory concentration index. Determination of the usefulness of combination treatments in patients needs well-conducted clinical trials, which are difficult. It is therefore important to study antifungal combinations in vivo, in experimental animal models of fungal infections. Although mammalian models have mostly been used, new alternative animal models in invertebrates look promising. To evaluate the antifungal efficacy, the most commonly used criteria are the mortality rate and the fungal load in the target organs.

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“…When resistance to not only azoles but also to other classes of antifungal drugs develops, a combination therapy is used. For example, the combined effect of amphotericin B and caspofungin [15], caspofungin and posaconazole [16], or isavuconazole and micafungin [17] have shown efficacy in overcoming the multi-drug resistance of the Candida species.…”

Section: Introductionmentioning

confidence: 99%

Molecular Cloning, Heterologous Expression, Purification, and Evaluation of Protein–Ligand Interactions of CYP51 of Candida krusei Azole-Resistant Fungal Strain

Tsybruk,

Kaluzhskiy,

Mezentsev

et al. 2023

Biomedicines

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Due to the increasing prevalence of fungal diseases caused by fungi of the genus Candida and the development of pathogen resistance to available drugs, the need to find new effective antifungal agents has increased. Azole antifungals, which are inhibitors of sterol-14α-demethylase or CYP51, have been widely used in the treatment of fungal infections over the past two decades. Of special interest is the study of C. krusei CYP51, since this fungus exhibit resistance not only to azoles, but also to other antifungal drugs and there is no available information about the ligand-binding properties of CYP51 of this pathogen. We expressed recombinant C. krusei CYP51 in E. coli cells and obtained a highly purified protein. Application of the method of spectrophotometric titration allowed us to study the interaction of C. krusei CYP51 with various ligands. In the present work, the interaction of C. krusei CYP51 with azole inhibitors, and natural and synthesized steroid derivatives was evaluated. The obtained data indicate that the resistance of C. krusei to azoles is not due to the structural features of CYP51 of this microorganism, but rather to another mechanism. Promising ligands that demonstrated sufficiently strong binding in the micromolar range to C. krusei CYP51 were identified, including compounds 99 (Kd = 1.02 ± 0.14 µM) and Ch-4 (Kd = 6.95 ± 0.80 µM). The revealed structural features of the interaction of ligands with the active site of C. krusei CYP51 can be taken into account in the further development of new selective modulators of the activity of this enzyme.

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OUP accepted manuscript

Cited by 17 publications

References 45 publications

Promising antifungal activity of new oxadiazole against Candida krusei

Promising antifungal activity of new oxadiazole against Candida krusei

Techniques for the Assessment of In Vitro and In Vivo Antifungal Combinations

Molecular Cloning, Heterologous Expression, Purification, and Evaluation of Protein–Ligand Interactions of CYP51 of Candida krusei Azole-Resistant Fungal Strain

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