scholarly journals Novel Regulatory Mechanisms of Pathogenicity and Virulence to Combat MDR inCandida albicans

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Saif Hameed ◽  
Zeeshan Fatima
Keyword(s):  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Opportunistic Pathogen ◽  
Antifungal Drugs ◽  
Regulatory Mechanisms ◽  
Cross Resistance ◽  
Signaling Networks ◽  
Antifungal Drug Resistance ◽  
Human Fungal Pathogen ◽  
Major Factors

Continuous deployment of antifungals in treating infections caused by dimorphic opportunistic pathogenCandida albicanshas led to the emergence of drug resistance resulting in cross-resistance to many unrelated drugs, a phenomenon termed multidrug resistance (MDR). Despite the current understanding of major factors which contribute to MDR mechanisms, there are many lines of evidence suggesting that it is a complex interplay of multiple factors which may be contributed by still unknown mechanisms. Coincidentally with the increased usage of antifungal drugs, the number of reports for antifungal drug resistance has also increased which further highlights the need for understanding novel molecular mechanisms which can be explored to combat MDR, namely, ROS, iron, hypoxia, lipids, morphogenesis, and transcriptional and signaling networks. Considering the worrying evolution of MDR and significance ofC. albicansbeing the most prevalent human fungal pathogen, this review summarizes these new regulatory mechanisms which could be exploited to prevent MDR development inC. albicansas established from recent studies.

scholarly journals Effects of Azole Antifungal Drugs on the Transition from Yeast Cells to Hyphae in Susceptible and Resistant Isolates of the Pathogenic Yeast Candida albicans

1999 ◽  
Vol 43 (4) ◽  
pp. 763-768 ◽  
Author(s):  
Kien C. Ha ◽  
Theodore C. White
Keyword(s):  
Drug Resistance ◽  
Candida Albicans ◽  
Molecular Mechanisms ◽  
Opportunistic Infections ◽  
Antifungal Drugs ◽  
Yeast Cells ◽  
Pathogenic Yeast ◽  
Oral Infections ◽  
Antifungal Drug Resistance ◽  
Hyphal Formation

ABSTRACT Oral infections caused by the yeast Candida albicansare some of the most frequent and earliest opportunistic infections in human immunodeficiency virus-infected patients. The widespread use of azole antifungal drugs has led to the development of drug resistance, creating a major problem in the treatment of yeast infections in AIDS patients and other immunocompromised individuals. Several molecular mechanisms that contribute to drug resistance have been identified. InC. albicans, the ability to morphologically switch from yeast cells (blastospores) to filamentous forms (hyphae) is an important virulence factor which contributes to the dissemination ofCandida in host tissues and which promotes infection and invasion. A positive correlation between the level of antifungal drug resistance and the ability to form hyphae in the presence of azole drugs has been identified. Under hypha-inducing conditions in the presence of an azole drug, resistant clinical isolates form hyphae, while susceptible yeast isolates do not. This correlation is observed in a random sample from a population of susceptible and resistant isolates and is independent of the mechanisms of resistance.35S-methionine incorporation suggests that growth inhibition is not sufficient to explain the inhibition of hyphal formation, but it may contribute to this inhibition.

Antimycotic drugs and their mechanisms of resistance to Candida species

2021 ◽  
Vol 22 ◽  
Author(s):  
Sweety Dahiya ◽  
Namita Sharma ◽  
Aruna Punia ◽  
Pooja Choudhary ◽  
Prity Gulia ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Candida Species ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
Treatment Strategies ◽  
Distinct Species ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Success Rates ◽  
Antifungal Drug Resistance

: Fungal infections have shown an upsurge in recent decades, mainly because of the increasing number of immunocompromised patients, and the occurrence of invasive candidiasis is found to be 7-15 folds greater than that of invasive aspergillosis. The genus Candida comprises of more than 150 distinct species; however, only a few of them are found to be pathogenic to humans. Mortality rates of Candida species are found to be around 45%, and the reasons for this intensified mortality are inefficient diagnostic techniques and unfitting initial treatment strategies. There are only a few antifungal drug classes that are employed for the remedy of invasive fungal infections, including azoles, polyenes, echinocandins, and pyrimidine analogs. During the last 2-3 decades, the usage of antifungal drugs has increased several folds, due to which the reports of escalating antifungal drug resistance have also been recorded. The resistance is mostly to the triazole-based compounds. Due to antifungal drug resistance, the success rates of treatment have been reduced and major changes have been observed in the frequency of fungal infections. In this review, we have summarized the major molecular mechanisms for the development of antifungal drug resistance.

scholarly journals Dysfunction of Prohibitin 2 Results in Reduced Susceptibility to Multiple Antifungal Drugs via Activation of the Oxidative Stress-Responsive Transcription Factor Pap1 in Fission Yeast

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Qiannan Liu ◽  
Fan Yao ◽  
Guanglie Jiang ◽  
Min Xu ◽  
Si Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Drug Resistance ◽  
Transcription Factor ◽  
Fission Yeast ◽  
Mitochondrial Protein ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Gene Encoding ◽  
Content Type ◽  
Antifungal Drug Resistance

ABSTRACT The fight against resistance to antifungal drugs requires a better understanding of the underlying cellular mechanisms. In order to gain insight into the mechanisms leading to antifungal drug resistance, we performed a genetic screen on a model organism, Schizosaccharomyces pombe, to identify genes whose overexpression caused resistance to antifungal drugs, including clotrimazole and terbinafine. We identified the phb2+ gene, encoding a highly conserved mitochondrial protein, prohibitin (Phb2), as a novel determinant of reduced susceptibility to multiple antifungal drugs. Unexpectedly, deletion of the phb2+ gene also exhibited antifungal drug resistance. Overexpression of the phb2+ gene failed to cause drug resistance when the pap1+ gene, encoding an oxidative stress-responsive transcription factor, was deleted. Furthermore, pap1+ mRNA expression was significantly increased when the phb2+ gene was overexpressed or deleted. Importantly, either overexpression or deletion of the phb2+ gene stimulated the synthesis of NO and reactive oxygen species (ROS), as measured by the cell-permeant fluorescent NO probe DAF-FM DA (4-amino-5-methylamino-2′,7′-difluorofluorescein diacetate) and the ROS probe DCFH-DA (2′,7′-dichlorodihydrofluorescein diacetate), respectively. Taken together, these results suggest that Phb2 dysfunction results in reduced susceptibility to multiple antifungal drugs by increasing NO and ROS synthesis due to dysfunctional mitochondria, thereby activating the transcription factor Pap1 in fission yeast.

scholarly journals Examining Signatures of Natural Selection in Antifungal Resistance Genes Across Aspergillus Fungi

2021 ◽  
Vol 2 ◽  
Author(s):  
Renato Augusto Corrêa dos Santos ◽  
Matthew E. Mead ◽  
Jacob L. Steenwyk ◽  
Olga Rivero-Menéndez ◽  
Ana Alastruey-Izquierdo ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Natural Selection ◽  
Positive Selection ◽  
Resistance Genes ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Sequence Evolution ◽  
Antifungal Drug Resistance ◽  
Selective Pressures ◽  
Substantial Heterogeneity

Certain Aspergillus fungi cause aspergillosis, a set of diseases that typically affect immunocompromised individuals. Most cases of aspergillosis are caused by Aspergillus fumigatus, which infects millions of people annually. Some closely related so-called cryptic species, such as Aspergillus lentulus, can also cause aspergillosis, albeit at lower frequencies, and they are also clinically relevant. Few antifungal drugs are currently available for treating aspergillosis and there is increasing worldwide concern about the presence of antifungal drug resistance in Aspergillus species. Furthermore, isolates from both A. fumigatus and other Aspergillus pathogens exhibit substantial heterogeneity in their antifungal drug resistance profiles. To gain insights into the evolution of antifungal drug resistance genes in Aspergillus, we investigated signatures of positive selection in 41 genes known to be involved in drug resistance across 42 susceptible and resistant isolates from 12 Aspergillus section Fumigati species. Using codon-based site models of sequence evolution, we identified ten genes that contain 43 sites with signatures of ancient positive selection across our set of species. None of the sites that have experienced positive selection overlap with sites previously reported to be involved in drug resistance. These results identify sites that likely experienced ancient positive selection in Aspergillus genes involved in resistance to antifungal drugs and suggest that historical selective pressures on these genes likely differ from any current selective pressures imposed by antifungal drugs.

scholarly journals Candida antifungal drug resistance in sub-Saharan African populations: A systematic review

F1000Research ◽  
2017 ◽  
Vol 5 ◽  
pp. 2832 ◽  
Author(s):  
Charlene Wilma Joyce Africa ◽  
Pedro Miguel dos Santos Abrantes
Keyword(s):  
Drug Resistance ◽  
Susceptibility Testing ◽  
Antifungal Susceptibility ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Sub Saharan Africa ◽  
African Countries ◽  
Antifungal Drug Resistance ◽  
Resistance Patterns ◽  
Sub Saharan

Background:Candidainfections are responsible for increased morbidity and mortality rates in at-risk patients, especially in developing countries where there is limited access to antifungal drugs and a high burden of HIV co-infection. Objectives:This study aimed to identify antifungal drug resistance patterns within the subcontinent of Africa. Methods: A literature search was conducted on published studies that employed antifungal susceptibility testing on clinicalCandidaisolates from sub-Saharan African countries using Pubmed and Google Scholar. Results: A total of 21 studies from 8 countries constituted this review. Only studies conducted in sub-Saharan Africa and employing antifungal drug susceptibility testing were included. Regional differences inCandidaspecies prevalence and resistance patterns were identified. Discussion: The outcomes of this review highlight the need for a revision of antifungal therapy guidelines in regions most affected byCandidadrug resistance.  Better controls in antimicrobial drug distribution and the implementation of regional antimicrobial susceptibility surveillance programmes are required in order to reduce the highCandidadrug resistance levels seen to be emerging in sub-Saharan Africa.

scholarly journals Candida parapsilosis: from Genes to the Bedside

2019 ◽  
Vol 32 (2) ◽  
Author(s):  
Renáta Tóth ◽  
Jozef Nosek ◽  
Héctor M. Mora-Montes ◽  
Toni Gabaldon ◽  
Joseph M. Bliss ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Candida Parapsilosis ◽  
Molecular Genetic ◽  
Antifungal Susceptibility ◽  
Resistance Mechanisms ◽  
Antifungal Drugs ◽  
Host Responses ◽  
Content Type ◽  
Antifungal Drug Resistance ◽  
Geographical Regions

SUMMARYPatients with suppressed immunity are at the highest risk for hospital-acquired infections. Among these, invasive candidiasis is the most prevalent systemic fungal nosocomial infection. Over recent decades, the combined prevalence of non-albicans Candidaspecies outrankedCandida albicansinfections in several geographical regions worldwide, highlighting the need to understand their pathobiology in order to develop effective treatment and to prevent future outbreaks.Candida parapsilosisis the second or third most frequently isolatedCandidaspecies from patients. Besides being highly prevalent, its biology differs markedly from that ofC. albicans, which may be associated withC. parapsilosis’ increased incidence. Differences in virulence, regulatory and antifungal drug resistance mechanisms, and the patient groups at risk indicate that conclusions drawn fromC. albicanspathobiology cannot be simply extrapolated toC. parapsilosis. Such species-specific characteristics may also influence their recognition and elimination by the host and the efficacy of antifungal drugs. Due to the availability of high-throughput, state-of-the-art experimental tools and molecular genetic methods adapted toC. parapsilosis, genome and transcriptome studies are now available that greatly contribute to our understanding of what makes this species a threat. In this review, we summarize 10 years of findings onC. parapsilosispathogenesis, including the species’ genetic properties, transcriptome studies, host responses, and molecular mechanisms of virulence. Antifungal susceptibility studies and clinician perspectives are discussed. We also present regional incidence reports in order to provide an updated worldwide epidemiology summary.

scholarly journals Pathogenesis and Antifungal Drug Resistance of the Human Fungal Pathogen Candida glabrata

2011 ◽  
Vol 4 (1) ◽  
pp. 169-186 ◽  
Author(s):  
Michael Tscherner ◽  
Tobias Schwarzmüller ◽  
Karl Kuchler
Keyword(s):  
Drug Resistance ◽  
Fungal Pathogen ◽  
Candida Glabrata ◽  
Antifungal Drug ◽  
Antifungal Drug Resistance ◽  
Human Fungal Pathogen

scholarly journals Transposon mobilization in the human fungal pathogen Cryptococcus is mutagenic during infection and promotes drug resistance in vitro

2020 ◽  
Vol 117 (18) ◽  
pp. 9973-9980 ◽  
Author(s):  
Asiya Gusa ◽  
Jonathan D. Williams ◽  
Jang-Eun Cho ◽  
Anna Floyd Averette ◽  
Sheng Sun ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Target Genes ◽  
Opportunistic Infections ◽  
Temperature Shift ◽  
Antifungal Drugs ◽  
Rnai Pathway ◽  
Human Pathogens ◽  
Human Fungal Pathogen

When transitioning from the environment, pathogenic microorganisms must adapt rapidly to survive in hostile host conditions. This is especially true for environmental fungi that cause opportunistic infections in immunocompromised patients since these microbes are not well adapted human pathogens. Cryptococcus species are yeastlike fungi that cause lethal infections, especially in HIV-infected patients. Using Cryptococcus deneoformans in a murine model of infection, we examined contributors to drug resistance and demonstrated that transposon mutagenesis drives the development of 5-fluoroorotic acid (5FOA) resistance. Inactivation of target genes URA3 or URA5 primarily reflected the insertion of two transposable elements (TEs): the T1 DNA transposon and the TCN12 retrotransposon. Consistent with in vivo results, increased rates of mutagenesis and resistance to 5FOA and the antifungal drugs rapamycin/FK506 (rap/FK506) and 5-fluorocytosine (5FC) were found when Cryptococcus was incubated at 37° compared to 30° in vitro, a condition that mimics the temperature shift that occurs during the environment-to-host transition. Inactivation of the RNA interference (RNAi) pathway, which suppresses TE movement in many organisms, was not sufficient to elevate TE movement at 30° to the level observed at 37°. We propose that temperature-dependent TE mobilization in Cryptococcus is an important mechanism that enhances microbial adaptation and promotes pathogenesis and drug resistance in the human host.

scholarly journals Candida tropicalis Antifungal Cross-Resistance Is Related to Different Azole Target (Erg11p) Modifications

2013 ◽  
Vol 57 (10) ◽  
pp. 4769-4781 ◽  
Author(s):  
A. Forastiero ◽  
A. C. Mesa-Arango ◽  
A. Alastruey-Izquierdo ◽  
L. Alcazar-Fuoli ◽  
L. Bernal-Martinez ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Amphotericin B ◽  
Candida Tropicalis ◽  
Antifungal Drug ◽  
Cross Resistance ◽  
Clinical Samples ◽  
Content Type ◽  
Antifungal Drug Resistance

ABSTRACTCandida tropicalisranks between third and fourth amongCandidaspecies most commonly isolated from clinical specimens. Invasive candidiasis and candidemia are treated with amphotericin B or echinocandins as first-line therapy, with extended-spectrum triazoles as acceptable alternatives.Candida tropicalisis usually susceptible to all antifungal agents, although several azole drug-resistant clinical isolates are being reported. However,C. tropicalisresistant to amphotericin B is uncommon, and only a few strains have reliably demonstrated a high level of resistance to this agent. The resistance mechanisms operating inC. tropicalisstrains isolated from clinical samples showing resistance to azole drugs alone or with amphotericin B cross-resistance were elucidated. Antifungal drug resistance was related to mutations of the azole target (Erg11p) with or without alterations of the ergosterol biosynthesis pathway. The antifungal drug resistance shownin vitrocorrelated very well with the results obtainedin vivousing the model hostGalleria mellonella. Using this panel of strains, theG. mellonellamodel system was validated as a simple, nonmammalian minihost model that can be used to studyin vitro-in vivocorrelation of antifungals inC. tropicalis. The development inC. tropicalisof antifungal drug resistance with different mechanisms during antifungal treatment has potential clinical impact and deserves specific prospective studies.

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