scholarly journals Participation of the ABC Transporter CDR1 in Azole Resistance of Candida lusitaniae

2021 ◽  
Vol 7 (9) ◽  
pp. 760
Author(s):  
Valentin Borgeat ◽  
Danielle Brandalise ◽  
Frédéric Grenouillet ◽  
Dominique Sanglard
Keyword(s):  
Abc Transporter ◽  
Dominant Role ◽  
Opportunistic Pathogen ◽  
Antifungal Drugs ◽  
Resistant Isolate ◽  
Azole Resistance ◽  
Fluconazole Resistance ◽  
Candida Lusitaniae ◽  
Major Facilitator

Candida lusitaniae is an opportunistic pathogen in humans that causes infrequent but difficult-to-treat diseases. Antifungal drugs are used in the clinic to treat C. lusitaniae infections, however, this fungus can rapidly acquire antifungal resistance to all known antifungal drugs (multidrug resistance). C. lusitaniae acquires azole resistance by gain-of-function (GOF) mutations in the transcriptional regulator MRR1. MRR1 controls the expression of a major facilitator transporter (MFS7) that is important for fluconazole resistance. Here, we addressed the role of the ATP Binding Cassette (ABC) transporter CDR1 as additional mediator of azole resistance in C. lusitaniae. CDR1 expression in isolates with GOF MRR1 mutations was higher compared to wild types, which suggests that CDR1 is an additional (direct or indirect) target of MRR1. CDR1 deletion in the azole-resistant isolate P3 (V688G GOF) revealed that MICs of long-tailed azoles, itraconazole and posaconazole, were decreased compared to P3, which is consistent with the role of this ABC transporter in the efflux of these azoles. Fluconazole MIC was only decreased when CDR1 was deleted in the background of an mfs7Δ mutant from P3, which underpins the dominant role of MFS7 in the resistance of the short-tailed azole fluconazole. With R6G efflux readout as Cdr1 efflux capacity, our data showed that R6G efflux was increased in P3 compared to an azole-susceptible wild type parent, and diminished to background levels in mutant strains lacking CDR1. Milbemycin oxim A3, a known inhibitor of fungal ABC transporters, mimicked efflux phenotypes of cdr1Δ mutants. We therefore provided evidence that CDR1 is an additional mediator of azole resistance in C. lusitaniae, and that CDR1 regulation is dependent on MRR1 and associated GOF mutations.

scholarly journals Increased mRNA levels of ERG16, CDR, and MDR1 correlate with increases in azole resistance in Candida albicans isolates from a patient infected with human immunodeficiency virus.

1997 ◽  
Vol 41 (7) ◽  
pp. 1482-1487 ◽  
Author(s):  
T C White
Keyword(s):  
Human Immunodeficiency Virus ◽  
Candida Albicans ◽  
Abc Transporter ◽  
Genetic Alterations ◽  
Antifungal Drugs ◽  
Cross Resistance ◽  
Mrna Levels ◽  
Fluconazole Resistance ◽  
Immunodeficiency Virus ◽  
Major Facilitator

Resistance to antifungal drugs, specifically azoles such as fluconazole, in the opportunistic yeast Candida albicans has become an increasing problem in human immunodeficiency virus (HIV)-infected individuals. The molecular mechanisms responsible for this resistance have only recently become apparent and can include alterations in the target enzyme of the azole drugs (lanosterol 14alpha demethylase [14DM]), or in various efflux pumps from both the ABC transporter and major facilitator gene families. To determine which of these possible mechanisms was associated with the development of drug resistance in a particular case, mRNA levels have been studied in a series of 17 clinical isolates taken from a single HIV-infected patient over 2 years, during which time the levels of fluconazole resistance of the strain increased over 200-fold. Using Northern blot analysis of steady-state levels of total RNA from these isolates, we observed increased mRNA levels of ERG16 (the 14DM-encoding gene), CDR1 (an ABC transporter), and MDR1 (a major facilitator) in this series. The timing of the increase in mRNA levels of each of these genes correlated with increases in fluconazole resistance of the isolates. Increased mRNA levels were not observed for three other ABC transporters, two other genes in the ergosterol biosynthetic pathway, or the NADPH-cytochrome P-450 oxidoreductase gene that transfers electrons from NADPH to 14DM. Increases in mRNA levels of ERG16 and CDR1 correlated with increased cross-resistance to ketoconazole and itraconazole but not to amphotericin B. A compilation of the genetic alterations identified in this series suggests that resistance develops gradually and is the sum of several different changes, all of which contribute to the final resistant phenotype.

scholarly journals Loss of Upc2p-InducibleERG3Transcription Is Sufficient To Confer Niche-Specific Azole Resistance without CompromisingCandida albicansPathogenicity

mBio ◽  
2018 ◽  
Vol 9 (3) ◽  
Author(s):  
Arturo Luna-Tapia ◽  
Hubertine M. E. Willems ◽  
Josie E. Parker ◽  
Hélène Tournu ◽  
Katherine S. Barker ◽  
...  
Keyword(s):  
Mouse Model ◽  
Stress Tolerance ◽  
Clinical Setting ◽  
Hyphal Growth ◽  
Antifungal Drugs ◽  
Azole Resistance ◽  
Fluconazole Resistance ◽  
Content Type ◽  
Disseminated Infection

ABSTRACTInactivation of sterol Δ5,6-desaturase (Erg3p) in the prevalent fungal pathogenCandida albicansis one of several mechanisms that can confer resistance to the azole antifungal drugs. However, loss of Erg3p activity is also associated with deficiencies in stress tolerance, invasive hyphal growth, and attenuated virulence in a mouse model of disseminated infection. This may explain why relatively fewerg3-deficient strains have been reported among azole-resistant clinical isolates. In this study, we examined the consequences of Erg3p inactivation uponC. albicanspathogenicity and azole susceptibility in mouse models of mucosal and disseminated infection. While aC. albicanserg3Δ/Δ mutant was unable to cause lethality in the disseminated model, it induced pathology in a mouse model of vaginal infection. Theerg3Δ/Δ mutant was also more resistant to fluconazole treatment than the wild type in both models of infection. Thus, complete loss of Erg3p activity confers azole resistance but also niche-specific virulence deficiencies. Serendipitously, we discovered that loss of azole-inducibleERG3transcription (rather than complete inactivation) is sufficient to conferin vitrofluconazole resistance, without compromisingC. albicansstress tolerance, hyphal growth, or pathogenicity in either mouse model. It is also sufficient to confer fluconazole resistance in the mouse vaginal model, but not in the disseminated model of infection, and thus confers niche-specific azole resistance without compromisingC. albicanspathogenicity at either site. Collectively, these results establish that modulating Erg3p expression or activity can have niche-specific consequences on bothC. albicanspathogenicity and azole resistance.IMPORTANCEWhile conferring resistance to the azole antifungalsin vitro, loss of sterol Δ5,6-desaturase (Erg3p) activity has also been shown to reduceC. albicanspathogenicity. Accordingly, it has been presumed that this mechanism may not be significant in the clinical setting. The results presented here challenge this assumption, revealing a more complex relationship between Erg3p activity, azole resistance,C. albicanspathogenicity, and the specific site of infection. Most importantly, we have shown that even modest changes inERG3transcription are sufficient to confer azole resistance without compromisingC. albicansfitness or pathogenicity. Given that previous efforts to assess the importance ofERG3as a determinant of clinical azole resistance have focused almost exclusively on detecting null mutants, its role may have been grossly underestimated. On the basis of our results, a more thorough investigation of the contribution of theERG3gene to azole resistance in the clinical setting is warranted.

scholarly journals Multiple mechanisms impact fluconazole resistance of mutant Erg11 proteins in Candida glabrata

2021 ◽  
Author(s):  
Bao Vu ◽  
W. Scott Moye-Rowley
Keyword(s):  
Transcription Factor ◽  
Candida Glabrata ◽  
Double Mutant ◽  
Antifungal Drugs ◽  
Cross Resistance ◽  
Ergosterol Biosynthesis ◽  
Azole Resistance ◽  
Pathogenic Yeast ◽  
Fluconazole Resistance ◽  
Growth Defects

Azoles remain the most common used antifungal drugs for invasive candidiasis worldwide. They specifically inhibit the fungal lanosterol a-14 demethylase enzyme, which is commonly referred to as Erg11 in fungi. Inhibition of Erg11 ultimately leads to a reduction in ergosterol production, an essential fungal membrane sterol. Many Candida species, such as Candida albicans, develop mutations in this enzyme which reduces the azole binding affinity and results in increased azole resistance. Candida glabrata is also a pathogenic yeast that has a low intrinsic susceptibility to azole drugs and easily develops elevated resistance. These azole resistant mutations are almost exclusively found to cause hyperactivity of the Pdr1 transcription factor and rarely lie within the ERG11 gene. Here, we generated C. glabrata ERG11 mutations that were analogous to azole resistance associated mutations in C. albicans ERG11. Three different Erg11 forms (Y141H, S410F, and the corresponding double mutant (DM)) conferred azole resistance in C. glabrata with the DM Erg11 form causing the strongest phenotype. The DM Erg11 also induced cross-resistance to amphotericin B and caspofungin. The azole resistance caused by the DM allele of ERG11 imposed a fitness cost that was not observed with hyperactive PDR1 alleles. These data support the view that C. glabrata does not typically acquire ERG11 mutations owing to growth defects associated with these lesions while hyperactive PDR1 alleles have no obvious growth issues. Understanding the physiology linking ergosterol biosynthesis with Pdr1-mediated regulation of azole resistance is crucial for ensuring the continued efficacy of azole drugs against C. glabrata.

scholarly journals Azole Resistance of Environmental and Clinical Aspergillus fumigatus Isolates from Switzerland

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Arnaud Riat ◽  
Jérôme Plojoux ◽  
Katia Gindro ◽  
Jacques Schrenzel ◽  
Dominique Sanglard
Keyword(s):  
Aspergillus Fumigatus ◽  
Opportunistic Pathogen ◽  
Clinical Isolates ◽  
Resistant Isolate ◽  
Azole Resistance ◽  
Clinical Settings ◽  
Content Type ◽  
Azole Antifungals ◽  
First Time

ABSTRACT Aspergillus fumigatus is a ubiquitous opportunistic pathogen. This fungus can acquire resistance to azole antifungals due to mutations in the azole target ( cyp51A ). Recently, cyp51A mutations typical for environmental azole resistance acquisition (for example, TR 34 /L98H) have been reported. These mutations can also be found in isolates recovered from patients. Environmental azole resistance acquisition has been reported on several continents. Here we describe, for the first time, the occurrence of azole-resistant A. fumigatus isolates of environmental origin in Switzerland with cyp51A mutations, and we show that these isolates can also be recovered from a few patients. While the TR 34 /L98H mutation was dominant, a single azole-resistant isolate exhibited a cyp51A mutation (G54R) that was reported only for clinical isolates. In conclusion, our study demonstrates that azole resistance with an environmental signature is present in environments and patients of Swiss origin and that mutations believed to be unique to clinical settings are now also observed in the environment.

scholarly journals A Transcriptomics Approach To Unveiling the Mechanisms ofIn VitroEvolution towards Fluconazole Resistance of aCandida glabrataClinical Isolate

2018 ◽  
Vol 63 (1) ◽  
Author(s):  
Mafalda Cavalheiro ◽  
Catarina Costa ◽  
Ana Silva-Dias ◽  
Isabel M. Miranda ◽  
Can Wang ◽  
...  
Keyword(s):  
Fungal Pathogen ◽  
Biofilm Formation ◽  
Molecular Mechanisms ◽  
Antifungal Drugs ◽  
Azole Resistance ◽  
Fluconazole Resistance ◽  
Content Type ◽  
Antifungal Drug Resistance ◽  
Genes Encoding ◽  
Multidrug Resistance Transporters

ABSTRACTCandida glabratais an emerging fungal pathogen. Its increased prevalence is associated with its ability to rapidly develop antifungal drug resistance, particularly to azoles. In order to unravel new molecular mechanisms behind azole resistance, a transcriptomics analysis of the evolution of aC. glabrataclinical isolate (isolate 044) from azole susceptibility to posaconazole resistance (21st day), clotrimazole resistance (31st day), and fluconazole and voriconazole resistance (45th day), induced by longstanding incubation with fluconazole, was carried out. All the evolved strains were found to accumulate lower concentrations of azole drugs than the parental strain, while the ergosterol concentration remained mostly constant. However, only the population displaying resistance to all azoles was found to have a gain-of-function mutation in theC. glabrataPDR1gene, leading to the upregulation of genes encoding multidrug resistance transporters. Intermediate strains, exhibiting posaconazole/clotrimazole resistance and increased fluconazole/voriconazole MIC levels, were found to display alternative ways to resist azole drugs. Particularly, posaconazole/clotrimazole resistance after 31 days was correlated with increased expression of adhesin genes. This finding led us to identify the Epa3 adhesin as a new determinant of azole resistance. Besides being required for biofilm formation, Epa3 expression was found to decrease the intracellular accumulation of azole antifungal drugs. Altogether, this work provides a glimpse of the transcriptomics evolution of aC. glabratapopulation toward multiazole resistance, highlighting the multifactorial nature of the acquisition of azole resistance and pointing out a new player in azole resistance.

Chronic Pain: Fundamental Scientific Considerations, Specifically for Legal Claims

2013 ◽  
Vol 18 (1) ◽  
pp. 1-18 ◽  
Author(s):  
Robert J. Barth
Keyword(s):  
Health Outcomes ◽  
Pain Perception ◽  
Driving Forces ◽  
Psychological Treatment ◽  
Dominant Role ◽  
Meta Analysis ◽  
General Medicine ◽  
Pain Syndrome ◽  
Problematic Relationship

Abstract Scientific findings have indicated that psychological and social factors are the driving forces behind most chronic benign pain presentations, especially in a claim context, and are relevant to at least three of the AMA Guides publications: AMA Guides to Evaluation of Disease and Injury Causation, AMA Guides to Work Ability and Return to Work, and AMA Guides to the Evaluation of Permanent Impairment. The author reviews and summarizes studies that have identified the dominant role of financial, psychological, and other non–general medicine factors in patients who report low back pain. For example, one meta-analysis found that compensation results in an increase in pain perception and a reduction in the ability to benefit from medical and psychological treatment. Other studies have found a correlation between the level of compensation and health outcomes (greater compensation is associated with worse outcomes), and legal systems that discourage compensation for pain produce better health outcomes. One study found that, among persons with carpal tunnel syndrome, claimants had worse outcomes than nonclaimants despite receiving more treatment; another examined the problematic relationship between complex regional pain syndrome (CRPS) and compensation and found that cases of CRPS are dominated by legal claims, a disparity that highlights the dominant role of compensation. Workers’ compensation claimants are almost never evaluated for personality disorders or mental illness. The article concludes with recommendations that evaluators can consider in individual cases.

НЕКОТОРЫЕ ОСОБЕННОСТИ РАСПРОСТРАНЕННОСТИ РЕСПИРАТОРНОЙ АЛЛЕРГИИ НА ЮГЕ РОССИИ

2019 ◽  
Author(s):  
D.Sh. Macharadze
Keyword(s):  
Dominant Role ◽  
Pollen Allergy ◽  
Respiratory Allergy ◽  
House Dust Mites ◽  
Dust Mites ◽  
The Past ◽  
Regional Features ◽  
Respiratory Allergies ◽  
Southern Russia

В обзорной статье приведены данные по распространенности респираторной аллергии - аллергического ринита и бронхиальной астмы на юге России, опубликованные за последние десятилетия. Показана доминирующая роль пыльцевой аллергии практически во всем южном регионе России. В Чеченской Республике у больных респираторной аллергией обнаружена сходная частота встречаемости сенсибилизации к клещам домашней пыли и пыльце злаковых трав (51,1 и 52,5 соответственно), тогда как сенсибилизация к пыльце амброзии и полыни встречалась в 3 раза реже (26,6 и 20,7 соответственно) по сравнению с соседними регионами юга России. Эти данные демонстрируют климатогеографические, экологические и другие региональные особенности в распространении респираторной аллергии.The review article presents data on the prevalence of respiratory allergy - allergic rhinitis and bronchial asthma in southern Russia, published over the past decades. The dominant role of pollen allergy is shown in almost the entire southern region of Russia. In the Chechen Republic, sensitization to house dust mites and grass pollen was found in patients with respiratory allergy equally (51.1 and 52.5, respectively), whereas ragweed and mugwort sensitization was 3 times less (26.6 and 20.7, respectively) compared with the neighboring regions of southern Russia. These data demonstrate climate-geographical, environmental and other regional features in the prevalence of respiratory allergies.

KEGAGALAN PRIVATISASI BUMN DI ERA REZIM ORDE BARU DALAM PERSPEKTIF EKONOMI POLITIK

Wacana Publik ◽  
2019 ◽  
Vol 12 (02) ◽  
Author(s):  
Syamsul Ma'arif
Keyword(s):  
Market Economy ◽  
Free Market ◽  
Dominant Role ◽  
The State ◽  
Early Years ◽  
New Order ◽  
Free Market Economy ◽  
Economic Sectors ◽  
Role Of The State

After had being carried out nationalization and hostility against west countries, the New Order regime made important decision to change Indonesia economic direction from etatism system to free market economy. A set of policies were taken in order private sector could play major role in economic. However, when another economic sectors were reformed substantially, effords to reform the State Owned Enterprises had failed. The State Owned Enterprise, in fact, remained to play dominant role like early years of guided democracy era. Role of the State Owned Enterprises was more and more powerfull). The main problem of reforms finally lied on reality that vested interest of bureaucrats (civil or military) was so large that could’nt been overcome. 

Conclusion

2018 ◽  
Author(s):  
Ildar Garipzanov
Keyword(s):  
Cultural History ◽  
Middle Ages ◽  
Late Antiquity ◽  
Western Europe ◽  
Dominant Role ◽  
Ninth Century ◽  
Sources Of Authority ◽  
History Of ◽  
Historical Periods

The concluding chapter highlights how the cultural history of graphic signs of authority in late antiquity and the early Middle Ages encapsulated the profound transformation of political culture in the Mediterranean and Europe from approximately the fourth to ninth centuries. It also reflects on the transcendent sources of authority in these historical periods, and the role of graphic signs in highlighting this connection. Finally, it warns that, despite the apparent dominant role of the sign of the cross and cruciform graphic devices in providing access to transcendent protection and support in ninth-century Western Europe, some people could still employ alternative graphic signs deriving from older occult traditions in their recourse to transcendent powers.

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