Contributions of
            <i>yap1</i>
            Mutation and Subsequent
            <i>atrF</i>
            Upregulation to Voriconazole Resistance in Aspergillus flavus

Ukai, Yuuta; Kuroiwa, Miho; Kurihara, Naoko; Naruse, Hiroki; Homma, Tomoyuki; Maki, Hideki; Naito, Akira

doi:10.1128/aac.01216-18

Cited by 22 publications

(19 citation statements)

References 65 publications

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“…fumigatus clinical isolates lacking Cyp51A mutations [ 145 , 146 ]. A recent study showed that a laboratory-generated voriconazole-resistant Aspergillus flavus isolate carried an amino acid substitution in Yap1 L558T , which was associated with an overexpression of AtrF and voriconazole resistance [ 147 ]. New studies implicating various cellular components and pathways involved in azole resistance resulted in significant advances on the topic of azole resistance in A .…”

Section: Mechanisms Of Antifungal Resistancementioning

confidence: 99%

Drug-Resistant Fungi: An Emerging Challenge Threatening Our Limited Antifungal Armamentarium

et al. 2020

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The high clinical mortality and economic burden posed by invasive fungal infections (IFIs), along with significant agricultural crop loss caused by various fungal species, has resulted in the widespread use of antifungal agents. Selective drug pressure, fungal attributes, and host- and drug-related factors have counteracted the efficacy of the limited systemic antifungal drugs and changed the epidemiological landscape of IFIs. Species belonging to Candida, Aspergillus, Cryptococcus, and Pneumocystis are among the fungal pathogens showing notable rates of antifungal resistance. Drug-resistant fungi from the environment are increasingly identified in clinical settings. Furthermore, we have a limited understanding of drug class-specific resistance mechanisms in emerging Candida species. The establishment of antifungal stewardship programs in both clinical and agricultural fields and the inclusion of species identification, antifungal susceptibility testing, and therapeutic drug monitoring practices in the clinic can minimize the emergence of drug-resistant fungi. New antifungal drugs featuring promising therapeutic profiles have great promise to treat drug-resistant fungi in the clinical setting. Mitigating antifungal tolerance, a prelude to the emergence of resistance, also requires the development of effective and fungal-specific adjuvants to be used in combination with systemic antifungals.

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Section: Mechanisms Of Antifungal Resistancementioning

confidence: 99%

Drug-Resistant Fungi: An Emerging Challenge Threatening Our Limited Antifungal Armamentarium

et al. 2020

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“…These results suggest that overexpression of efflux pumps and target genes in those non-WT strains lacking mutations in the cyp51 gene can lead to high voriconazole MICs in clinical A. flavus isolates. It has also been reported that a mutation in yap1 (Leu558Trp) gene, the transcription factor involved in oxidative stress, is responsible for a voriconazole resistance phenotype which acts by upregulation of atrF transporter [127].…”

Section: Antifungal Resistancementioning

confidence: 99%

Invasive Aspergillosis by Aspergillus flavus: Epidemiology, Diagnosis, Antifungal Resistance, and Management

Rudramurthy

Paul

Chakrabarti

et al. 2019

JoF

194

143

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Aspergillus flavus is the second most common etiological agent of invasive aspergillosis (IA) after A. fumigatus. However, most literature describes IA in relation to A. fumigatus or together with other Aspergillus species. Certain differences exist in IA caused by A. flavus and A. fumigatus and studies on A. flavus infections are increasing. Hence, we performed a comprehensive updated review on IA due to A. flavus. A. flavus is the cause of a broad spectrum of human diseases predominantly in Asia, the Middle East, and Africa possibly due to its ability to survive better in hot and arid climatic conditions compared to other Aspergillus spp. Worldwide, ~10% of cases of bronchopulmonary aspergillosis are caused by A. flavus. Outbreaks have usually been associated with construction activities as invasive pulmonary aspergillosis in immunocompromised patients and cutaneous, subcutaneous, and mucosal forms in immunocompetent individuals. Multilocus microsatellite typing is well standardized to differentiate A. flavus isolates into different clades. A. flavus is intrinsically resistant to polyenes. In contrast to A. fumigatus, triazole resistance infrequently occurs in A. flavus and is associated with mutations in the cyp51C gene. Overexpression of efflux pumps in non-wildtype strains lacking mutations in the cyp51 gene can also lead to high voriconazole minimum inhibitory concentrations. Voriconazole remains the drug of choice for treatment, and amphotericin B should be avoided. Primary therapy with echinocandins is not the first choice but the combination with voriconazole or as monotherapy may be used when the azoles and amphotericin B are contraindicated.

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“…During 2-3 past decades, new antifungals including, voriconazole, posaconazole and caspofungin were licensed for the treatment of invasive aspergillosis (7,8). So that, voriconazole was presented as the first-line antifungal for invasive aspergillosis therapy (13,14). Also, caspofungin is recommended for invasive aspergillosis in AIDs patients (5).…”

Section: Introductionmentioning

confidence: 99%

“…Aspergillus flavus not only has the ability to causes primary infections in immunocompetent (16,17), but also cause invasive infections in chemotherapy users, invasive therapy, immunocompromised patients, organ transplant and hematopoietic stem cell recipients (8,14). In addition, A. flavus is one of the most important otomycosis agents (18).…”

Section: Introductionmentioning

confidence: 99%

The high efficacy of luliconazole against environmental and otomycosis Aspergillus flavus strains

Moslem

Mahmoudabadi

2020

IJM

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Background and Objectives: Luliconazole is currently confirmed for the topical therapy of dermatophytosis. Moreover, it is found that luliconazole has in vitro activity against some molds and yeast species. The aim of the present study was to evaluate the efficacy of luliconazole in comparison to routine used antifungals on clinical and environmental isolates of Aspergillus flavus. Materials and Methods: Thirty eight isolates of A. flavus (18 environmental and 20 clinical isolates) were detected based on morphological and microscopic features and also PCR-sequencing of β-tubulin ribosomal DNA gene. All the isolates were tested against luliconazole, voriconazole, amphotericin B and caspofungin. Minimum inhibitory concentration (MIC), 90 MIC50, MIC isolates. and MIC Geometric (GM) were calculated using CLSI M38-A2 protocol for both environmental and clinical GM Results: Luliconazole with extremely low MIC range, 0.00049-0.00781 μg/mL and MIC 0.00288 μg/mL showed very strong activity against both clinical and environmental A. flavus isolates. Moreover, voriconazole inhibited 100% of isolates at defined epidemiological cutoff values (ECV ≤ 2 µg/ml). 50% and 27.8% of clinical and environmental isolates of A. flavus, were resistant to caspofungin, respectively. Whereas, all the isolates were found to be resistant to amphotericin B. GM Conclusion: The analysis of our data clearly indicated that luliconazole (with MIC 0.00244 µg/ml for clinical and 0.00336 μg/ml for environmental isolates) had the highest in vitro activity against A. flavus strains.

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Contributions of yap1 Mutation and Subsequent atrF Upregulation to Voriconazole Resistance in Aspergillus flavus

Cited by 22 publications

References 65 publications

Drug-Resistant Fungi: An Emerging Challenge Threatening Our Limited Antifungal Armamentarium

Drug-Resistant Fungi: An Emerging Challenge Threatening Our Limited Antifungal Armamentarium

Invasive Aspergillosis by Aspergillus flavus: Epidemiology, Diagnosis, Antifungal Resistance, and Management

The high efficacy of luliconazole against environmental and otomycosis Aspergillus flavus strains

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