Mitochondrial Membrane-Associated Protein Mba1 Confers Antifungal Resistance by Affecting the Production of Reactive Oxygen Species in Aspergillus fumigatus

Zhu, Guangshan; Shu, Chang; Zhang, Yuanwei; Lü, Ling

doi:10.1128/aac.00225-23

Cited by 6 publications

(2 citation statements)

References 53 publications

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“…High MIC values for azoles can stem from various mechanisms leading to resistance in A. fumigatus, such as efflux pumps, hapE mutation, cholesterol import by A. fumigatus [53], and overexpression of the cyp51B gene [11]. Recently, it was revealed that a mutation in the mitochondrial ribosome-binding protein Mba1 can confer multidrug resistance to azoles [54]. These non-cyp51A mechanisms offer explanations for the existence of resistant A. fumigatus strains without mutations in the target gene for azole actions.…”

Section: Discussionmentioning

confidence: 99%

Uncovering a Novel cyp51A Mutation and Antifungal Resistance in Aspergillus fumigatus through Culture Collection Screening

Pontes,

Arai,

Gualtieri Beraquet

et al. 2024

JoF

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Background: Aspergillus fumigatus is an important concern for immunocompromised individuals, often resulting in severe infections. With the emergence of resistance to azoles, which has been the therapeutic choice for Aspergillus infections, monitoring the resistance of these microorganisms becomes important, including the search for mutations in the cyp51A gene, which is the gene responsible for the mechanism of action of azoles. We conducted a retrospective analysis covering 478 A. fumigatus isolates. Methods: This comprehensive dataset comprised 415 clinical isolates and 63 isolates from hospital environmental sources. For clinical isolates, they were evaluated in two different periods, from 1998 to 2004 and 2014 to 2021; for environmental strains, one strain was isolated in 1998, and 62 isolates were evaluated in 2015. Our primary objectives were to assess the epidemiological antifungal susceptibility profile; trace the evolution of resistance to azoles, Amphotericin B (AMB), and echinocandins; and monitor cyp51A mutations in resistant strains. We utilized the broth microdilution assay for susceptibility testing, coupled with cyp51A gene sequencing and microsatellite genotyping to evaluate genetic variability among resistant strains. Results: Our findings reveal a progressive increase in Minimum Inhibitory Concentrations (MICs) for azoles and AMB over time. Notably, a discernible trend in cyp51A gene mutations emerged in clinical isolates starting in 2014. Moreover, our study marks a significant discovery as we detected, for the first time, an A. fumigatus isolate carrying the recently identified TR46/F495I mutation within a sample obtained from a hospital environment. The observed cyp51A mutations underscore the ongoing necessity for surveillance, particularly as MICs for various antifungal classes continue to rise. Conclusions: By conducting resistance surveillance within our institution’s culture collection, we successfully identified a novel TR46/F495I mutation in an isolate retrieved from the hospital environment which had been preserved since 1998. Moreover, clinical isolates were found to exhibit TR34/L98H/S297T/F495I mutations. In addition, we observed an increase in MIC patterns for Amphotericin B and azoles, signaling a change in the resistance pattern, emphasizing the urgent need for the development of new antifungal drugs. Our study highlights the importance of continued monitoring and research in understanding the evolving challenges in managing A. fumigatus infections.

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Section: Discussionmentioning

confidence: 99%

Uncovering a Novel cyp51A Mutation and Antifungal Resistance in Aspergillus fumigatus through Culture Collection Screening

Pontes,

Arai,

Gualtieri Beraquet

et al. 2024

JoF

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“…[16][17][18] However, there are increasing reports of A. fumigatus strains that are resistant to clinical azoles despite lacking cyp51A modifications. 19,20 Extensive research has been conducted on strains with multiple mutations in hmg1 and hmg2, which encode the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. These mutations have provided valuable insights into the mechanism of azole drug resistance in A. fumigatus.…”

Section: Introductionmentioning

confidence: 99%

Epidemiology and Azole Resistance of Clinical Isolates of Aspergillus fumigatus from a Large Tertiary Hospital in Ningxia, China

Kang,

Li,

Yao

et al. 2024

IDR

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Purpose The objective of this study was to determine the clinical distribution, in vitro antifungal susceptibility and underlying resistance mechanisms of Aspergillus fumigatus ( A. fumigatus ) isolates from the General Hospital of Ningxia Medical University between November 2021 and May 2023. Methods Antifungal susceptibility testing was performed using the Sensititre YeastOne YO10, and isolates with high minimal inhibitory concentrations (MICs) were further confirmed using the standard broth microdilution assays established by the Clinical and Laboratory Standards Institute (CLSI) M38-third edition. Whole-Genome Resequencing and RT-qPCR in azole-resistant A. fumigatus strains were performed to investigate the underlying resistance mechanisms. Results Overall, a total of 276 A. fumigatus isolates were identified from various clinical departments, showing an increasing trend in the number of isolates over the past 3 years. Two azole-resistant A. fumigatus strains (0.72%) were observed, one of which showed overexpression of cyp51A, cyp51B, cdr1B, MDR1/2, artR, srbA, erg24A , and erg4B , but no cyp51A mutation. However, the other strain harbored two alterations in the cyp51A sequences (L98H/S297T). Therefore, we first described two azole-resistant clinical A. fumigatus strains in Ningxia, China, and reported one azole-resistant strain that has the L98H/S297T mutations in the cyp51A gene without any tandem repeat (TR) sequences in the promoter region. Conclusions This study emphasizes the importance of enhancing attention and surveillance of azole-resistant A. fumigatus , particularly those with non-TR point mutations of cyp51A or non- cyp51A mutations, in order to gain a better understanding of their prevalence and spread in the region.

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A ubiquitin-mediated post-translational degradation of Cyp51A contributes to a novel azole resistance mode in Aspergillus fumigatus

Zhu,

Fu,

Zhang

et al. 2024

Microbiological Research

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Mitochondrial Membrane-Associated Protein Mba1 Confers Antifungal Resistance by Affecting the Production of Reactive Oxygen Species in Aspergillus fumigatus

Cited by 6 publications

References 53 publications

Uncovering a Novel cyp51A Mutation and Antifungal Resistance in Aspergillus fumigatus through Culture Collection Screening

Uncovering a Novel cyp51A Mutation and Antifungal Resistance in Aspergillus fumigatus through Culture Collection Screening

Epidemiology and Azole Resistance of Clinical Isolates of Aspergillus fumigatus from a Large Tertiary Hospital in Ningxia, China

A ubiquitin-mediated post-translational degradation of Cyp51A contributes to a novel azole resistance mode in Aspergillus fumigatus

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