Transcription Factor CCG-8 as a New Regulator in the Adaptation to Antifungal Azole Stress

ABSTRACTAntifungal azoles are widely used for controlling fungal infections. Fungi are able to change the expression of many genes when they adapt to azole stress, and increased expression of some of these genes can elevate resistance to azoles. However, the regulatory mechanisms behind transcriptional adaption to azoles in filamentous fungi are poorly understood. In this study, we found that deletion of the transcription factor geneccg-8, which is known to be a clock-controlled gene, madeNeurospora crassahypersensitive to azoles. A comparative genome-wide analysis of the responses to ketoconazole of the wild type and theccg-8mutant revealed that the transcriptional responses to ketoconazole of 78 of the 488 transcriptionally ketoconazole-upregulated genes and the 427 transcriptionally ketoconazole-downregulated genes in the wild type were regulated by CCG-8. Ketoconazole sensitivity testing of all available knockout mutants for CCG-8-regulated genes revealed that CCG-8 contributed to azole adaption by regulating the ketoconazole responses of many genes, including the target gene (erg11), an azole transporter gene (cdr4), a hexose transporter gene (hxt13), a stress response gene (locus number NCU06317, namedkts-1), two transcription factor genes (NCU01386 [namedkts-2] andfsd-1/ndt80), four enzyme-encoding genes, and six unknown-function genes. CCG-8 also regulated phospholipid synthesis inN. crassain a manner similar to that of its homolog inSaccharomyces cerevisiae, Opi1p. However, there was no cross talk between phospholipid synthesis and azole resistance inN. crassa. CCG-8 homologs are conserved and are common in filamentous fungi. Deletion of the CCG-8 homolog-encoding gene inFusarium verticillioides(Fvccg-8) also made this fungus hypersensitive to antifungal azoles.

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Transcription Factor ADS-4 Regulates Adaptive Responses and Resistance to Antifungal Azole Stress

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00542-15 ◽

2015 ◽

Vol 59 (9) ◽

pp. 5396-5404 ◽

Cited By ~ 9

Author(s):

Kangji Wang ◽

Zhenying Zhang ◽

Xi Chen ◽

Xianyun Sun ◽

Cheng Jin ◽

...

Keyword(s):

Transcription Factor ◽

Efflux Pump ◽

Fungal Infections ◽

Antifungal Drugs ◽

Bzip Transcription Factor ◽

Azole Resistance ◽

Homologous Gene ◽

Adaptive Responses ◽

Transcriptional Responses ◽

Content Type

ABSTRACTAzoles are commonly used as antifungal drugs or pesticides to control fungal infections in medicine and agriculture. Fungi adapt to azole stress by rapidly activating the transcription of a number of genes, and transcriptional increases in some azole-responsive genes can elevate azole resistance. The regulatory mechanisms that control transcriptional responses to azole stress in filamentous fungi are not well understood. This study identified a bZIP transcription factor, ADS-4 (antifungaldrugsensitive-4), as a new regulator of adaptive responses and resistance to antifungal azoles. Transcription ofads-4inNeurospora crassacells increased when they were subjected to ketoconazole treatment, whereas the deletion ofads-4resulted in hypersensitivity to ketoconazole and fluconazole. In contrast, the overexpression ofads-4increased resistance to fluconazole and ketoconazole inN. crassa. Transcriptome sequencing (RNA-seq) analysis, followed by quantitative reverse transcription (qRT)-PCR confirmation, showed that ADS-4 positively regulated the transcriptional responses of at least six genes to ketoconazole stress inN. crassa. The gene products of four ADS-4-regulated genes are known contributors to azole resistance, including the major efflux pump CDR4 (Pdr5p ortholog), an ABC multidrug transporter (NcAbcB), sterol C-22 desaturase (ERG5), and a lipid transporter (NcRTA2) that is involved in calcineurin-mediated azole resistance. Deletion of theads-4-homologous gene Afads-4inAspergillus fumigatuscaused hypersensitivity to itraconazole and ketoconazole, which suggested that ADS-4 is a functionally conserved regulator of adaptive responses to azoles. This study provides important information on a new azole resistance factor that could be targeted by a new range of antifungal pesticides and drugs.

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Transcription Factor NsdD Regulates the Expression of Genes Involved in Plant Biomass-Degrading Enzymes, Conidiation, and Pigment Biosynthesis inPenicillium oxalicum

Applied and Environmental Microbiology ◽

10.1128/aem.01039-18 ◽

2018 ◽

Vol 84 (18) ◽

Cited By ~ 8

Author(s):

Qi-Peng He ◽

Shuai Zhao ◽

Jiu-Xiang Wang ◽

Cheng-Xi Li ◽

Yu-Si Yan ◽

...

Keyword(s):

Transcription Factor ◽

Genetic Engineering ◽

Filamentous Fungi ◽

Soil Fungi ◽

Plant Biomass ◽

Penicillium Oxalicum ◽

Content Type ◽

Cellular Processes ◽

Wide Range ◽

Pigment Biosynthesis

ABSTRACTSoil fungi produce a wide range of chemical compounds and enzymes with potential for applications in medicine and biotechnology. Cellular processes in soil fungi are highly dependent on the regulation under environmentally induced stress, but most of the underlying mechanisms remain unclear. Previous work identified a key GATA-type transcription factor,Penicillium oxalicumNsdD (PoxNsdD; also called POX08415), that regulates the expression of cellulase and xylanase genes inP. oxalicum. PoxNsdD shares 57 to 64% identity with the key activator NsdD, involved in asexual development inAspergillus. In the present study, the regulatory roles of PoxNsdD inP. oxalicumwere further explored. Comparative transcriptomic profiling revealed that PoxNsdD regulates major genes involved in starch, cellulose, and hemicellulose degradation, as well as conidiation and pigment biosynthesis. Subsequent experiments confirmed that a ΔPoxNsdDstrain lost 43.9 to 78.8% of starch-digesting enzyme activity when grown on soluble corn starch, and it produced 54.9 to 146.0% more conidia than the ΔPoxKu70parental strain. During cultivation, ΔPoxNsdDcultures changed color, from pale orange to brick red, while the ΔPoxKu70cultures remained bluish white. Real-time quantitative reverse transcription-PCR showed thatPoxNsdDdynamically regulated the expression of a glucoamylase gene (POX01356/Amy15A), an α-amylase gene (POX09352/Amy13A), and a regulatory gene (POX03890/amyR), as well as a polyketide synthase gene (POX01430/alb1/wA) for yellow pigment biosynthesis and a conidiation-regulated gene (POX06534/brlA). Moreover,in vitrobinding experiments showed that PoxNsdD bound the promoter regions of the above-described genes. This work provides novel insights into the regulatory mechanisms of fungal cellular processes and may assist in genetic engineering ofP.oxalicumfor potential industrial and medical applications.IMPORTANCEMost filamentous fungi produce a vast number of extracellular enzymes that are used commercially for biorefineries of plant biomass to produce biofuels and value-added chemicals, which might promote the transition to a more environmentally friendly economy. The expression of these extracellular enzyme genes is tightly controlled at the transcriptional level, which limits their yields. Hitherto our understanding of the regulation of expression of plant biomass-degrading enzyme genes in filamentous fungi has been rather limited. In the present study, regulatory roles of a key regulator, PoxNsdD, were further explored in the soil fungusPenicillium oxalicum, contributing to the understanding of gene regulation in filamentous fungi and revealing the biotechnological potential ofP.oxalicumvia genetic engineering.

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VibA, a Homologue of a Transcription Factor for Fungal Heterokaryon Incompatibility, Is Involved in Antifungal Compound Production in the Plant-Symbiotic Fungus Epichloë festucae

Eukaryotic Cell ◽

10.1128/ec.00034-14 ◽

2014 ◽

Vol 14 (1) ◽

pp. 13-24 ◽

Cited By ~ 14

Author(s):

Jennifer T. Niones ◽

Daigo Takemoto

Keyword(s):

Transcription Factor ◽

Antifungal Activity ◽

Critical Role ◽

Antifungal Compound ◽

Symbiotic Association ◽

Wild Type ◽

Exogenous Dna ◽

Content Type ◽

Type Isolate ◽

Epichloë Festucae

ABSTRACT Symbiotic association of epichloae endophytes ( Epichloë/Neotyphodium species) with cool-season grasses of the subfamily Pooideae confers bioprotective benefits to the host plants against abiotic and biotic stresses. While the production of fungal bioprotective metabolites is a well-studied mechanism of host protection from insect herbivory, little is known about the antibiosis mechanism against grass pathogens by the mutualistic endophyte. In this study, an Epichloë festucae mutant defective in antimicrobial substance production was isolated by a mutagenesis approach. In an isolated mutant that had lost antifungal activity, the exogenous DNA fragment was integrated into the promoter region of the vibA gene, encoding a homologue of the transcription factor VIB-1. VIB-1 in Neurospora crassa is a regulator of genes essential in vegetative incompatibility and promotion of cell death. Here we show that deletion of the vibA gene severely affected the antifungal activity of the mutant against the test pathogen Drechslera erythrospila . Further analyses showed that overexpressing vibA enhanced the antifungal activity of the wild-type isolate against test pathogens. Transformants overexpressing vibA showed an inhibitory activity on test pathogens that the wild-type isolate could not. Moreover, overexpressing vibA in a nonantifungal E. festucae wild-type Fl1 isolate enabled the transformant to inhibit the mycelial and spore germination of D. erythrospila . These results demonstrate that enhanced expression of vibA is sufficient for a nonantifungal isolate to obtain antifungal activity, implicating the critical role of VibA in antifungal compound production by epichloae endophytes.

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SAGA/ADA Complex Subunit Ada2 Is Required for Cap1- but Not Mrr1-Mediated Upregulation of the Candida albicans Multidrug Efflux PumpMDR1

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03065-14 ◽

2014 ◽

Vol 58 (9) ◽

pp. 5102-5110 ◽

Cited By ~ 16

Author(s):

Bernardo Ramírez-Zavala ◽

Selene Mogavero ◽

Eva Schöller ◽

Christoph Sasse ◽

P. David Rogers ◽

...

Keyword(s):

Transcription Factor ◽

Candida Albicans ◽

Efflux Pump ◽

Wild Type ◽

Multidrug Efflux ◽

Multidrug Efflux Pump ◽

Gain Of Function ◽

Content Type ◽

Zinc Cluster ◽

Fluconazole Resistant

ABSTRACTOverexpression of the multidrug efflux pumpMDR1is one mechanism by which the pathogenic yeastCandida albicansdevelops resistance to the antifungal drug fluconazole. The constitutive upregulation ofMDR1in fluconazole-resistant, clinicalC. albicansisolates is caused by gain-of-function mutations in the zinc cluster transcription factor Mrr1. It has been suggested that Mrr1 activatesMDR1transcription by recruiting Ada2, a subunit of the SAGA/ADA coactivator complex. However,MDR1expression is also regulated by the bZIP transcription factor Cap1, which mediates the oxidative stress response inC. albicans. Here, we show that a hyperactive Mrr1 containing a gain-of-function mutation promotesMDR1overexpression independently of Ada2. In contrast, a C-terminally truncated, hyperactive Cap1 causedMDR1overexpression in a wild-type strain but only weakly in mutants lackingADA2. In the presence of benomyl or H2O2, compounds that induceMDR1expression in an Mrr1- and Cap1-dependent fashion,MDR1was upregulated with the same efficiency in wild-type andada2Δ cells. These results indicate that Cap1, but not Mrr1, recruits Ada2 to theMDR1promoter to induce the expression of this multidrug efflux pump and that Ada2 is not required forMDR1overexpression in fluconazole-resistantC. albicansstrains containing gain-of-function mutations in Mrr1.

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Novel Cell-Killing Mechanisms of Hydroxyurea and the Implication toward Combination Therapy for the Treatment of Fungal Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00734-17 ◽

2017 ◽

Vol 61 (11) ◽

Cited By ~ 3

Author(s):

Amanpreet Singh ◽

Ameeta Agarwal ◽

Yong-jie Xu

Keyword(s):

Saccharomyces Cerevisiae ◽

Fungal Pathogen ◽

Fungal Infections ◽

Genetic Data ◽

Heme Biosynthesis ◽

Wild Type ◽

Content Type ◽

Ergosterol Synthesis ◽

Opportunistic Fungal Pathogen ◽

Cell Lethality

ABSTRACT We have previously reported that an erg11 mutation affecting ergosterol synthesis and a hem13 mutation in the heme synthesis pathway significantly sensitize the fission yeast Schizosaccharomyces pombe to hydroxyurea (HU) (1, 2). Here we show that treatment with inhibitors of Erg11 and heme biosynthesis phenocopies the two mutations in sensitizing wild-type cells to HU. Importantly, HU synergistically interacts with the heme biosynthesis inhibitor sampangine and several Erg11 inhibitors, the antifungal azoles, in causing cell lethality. Since the synergistic drug interactions are also observed in the phylogenetically divergent Saccharomyces cerevisiae and the opportunistic fungal pathogen Candida albicans, the synergism is likely conserved in eukaryotes. Interestingly, our genetic data for S. pombe has also led to the discovery of a robust synergism between sampangine and the azoles in C. albicans. Thus, combinations of HU, sampangine, and the azoles can be further studied as a new method for the treatment of fungal infections.

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In Vitro Activity of Manogepix against Multidrug-Resistant and Panresistant Candida auris from the New York Outbreak

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01124-20 ◽

2020 ◽

Vol 64 (11) ◽

Cited By ~ 1

Author(s):

YanChun Zhu ◽

Shannon Kilburn ◽

Mili Kapoor ◽

Sudha Chaturvedi ◽

Karen Joy Shaw ◽

...

Keyword(s):

New York ◽

Fungal Infections ◽

Geometric Mean ◽

Multidrug Resistant ◽

Antifungal Drugs ◽

New Drugs ◽

Wild Type ◽

Candida Auris ◽

Content Type

ABSTRACT An ongoing Candida auris outbreak in the New York metropolitan area is the largest recorded to date in North America. Laboratory surveillance revealed NY C. auris isolates are resistant to fluconazole, with variable resistance to other currently used broad-spectrum antifungal drugs, and that several isolates are panresistant. Thus, there is an urgent need for new drugs with a novel mechanism of action to combat the resistance challenge. Manogepix (MGX) is a first-in-class agent that targets the fungal Gwt1 enzyme. The prodrug fosmanogepix is currently in phase 2 clinical development for the treatment of fungal infections. We evaluated the susceptibility of 200 New York C. auris isolates to MGX and 10 comparator drugs using CLSI methodology. MGX demonstrated lower MICs than comparators (MIC50 and MIC90, 0.03 mg/liter; range, 0.004 to 0.06 mg/liter). The local epidemiological cutoff value (ECV) for MGX indicated all C. auris isolates were within the population of wild-type (WT) strains; 0.06 mg/liter defines the upper limit of wild type (UL-WT). MGX was 8- to 32-fold more active than the echinocandins, 16- to 64-fold more active than the azoles, and 64-fold more active than amphotericin B. No differences were found in the MGX or comparators’ MIC50, MIC90, or geometric mean (GM) values when subsets of clinical, surveillance, and environmental isolates were evaluated. The range of MGX MIC values for six C. auris panresistant isolates was 0.008 to 0.015 mg/liter, and the median and mode MIC values were 0.015 mg/liter, demonstrating that MGX retains activity against these isolates. These data support further clinical evaluation of fosmanogepix for the treatment of C. auris infections, including highly resistant isolates.

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HapX, an Indispensable bZIP Transcription Factor for Iron Acquisition, Regulates Infection Initiation by Orchestrating Conidial Oleic Acid Homeostasis and Cytomembrane Functionality in Mycopathogen Beauveria bassiana

mSystems ◽

10.1128/msystems.00695-20 ◽

2020 ◽

Vol 5 (5) ◽

Author(s):

Yue-Jin Peng ◽

Jia-Jia Wang ◽

Hai-Yan Lin ◽

Jin-Li Ding ◽

Ming-Guang Feng ◽

...

Keyword(s):

Transcription Factor ◽

Oleic Acid ◽

Fatty Acid ◽

Filamentous Fungi ◽

Beauveria Bassiana ◽

Iron Acquisition ◽

Membrane Integrity ◽

Fatty Acid Desaturase ◽

Bzip Transcription Factor ◽

Content Type

ABSTRACT In pathogenic filamentous fungi, conidial germination not only is fundamental for propagation in the environment but is also a critical step of infection. In the insect mycopathogen Beauveria bassiana, we genetically characterized the role of the basic leucine zipper (bZIP) transcription factor HapX (BbHapX) in conidial nutrient reserves and pathogen-host interaction. Ablation of BbHapX resulted in an almost complete loss of virulence in the topical inoculation and intrahemocoel injection assays. Comparative transcriptomic analysis revealed that BbHapX is required for fatty acid (FA)/lipid metabolism, and biochemical analyses indicated that BbHapX loss caused a significant reduction in conidial FA contents. Exogenous oleic acid could partially or completely restore the impaired phenotypes of the ΔBbHapX mutant, including germination rate, membrane integrity, vegetative growth, and virulence. BbHapX mediates fungal iron acquisition which is not required for desaturation of stearic acid. Additionally, inactivation of the Δ9-fatty acid desaturase gene (BbOle1) generated defects similar to those of the ΔBbHapX mutant; oleic acid also had significant restorative effects on the defective phenotypes of the ΔBbOle1 mutant. A gel retarding assay revealed that BbHapX directly regulated the expression of BbOle1. Lipidomic analyses indicated that both BbHapX and BbOle1 contributed to the homeostasis of phospholipids with nonpolar tails derived from oleic acid; therefore, exogenous phospholipids could significantly restore membrane integrity. These data reveal that the HapX-Ole1 pathway contributes to conidial fatty acid/lipid reserves and that there are important links between the lipid biology and membrane functionality involved in the early stages of infection caused by B. bassiana. IMPORTANCE Conidial maturation and germination are highly coupled physiological processes in filamentous fungi that are critical for the pathogenicity of mycopathogens. Compared to the mechanisms involved in conidial germination, those of conidial reserves during maturation are less understood. The insect-pathogenic fungus Beauveria bassiana, as a representative species of filamentous fungi, is important for applied and fundamental research. In addition to its conserved roles in fungal adaptation to iron status, the bZIP transcription factor HapX acts as a master regulator involved in conidial virulence and regulates fatty acid/lipid metabolism. Further investigation revealed that the Δ9-fatty acid desaturase gene (Ole1) is a direct downstream target of HapX. This study reveals the HapX-Ole1 pathway involved in the fatty acid/lipid accumulation associated with conidial maturation and provides new insights into the startup mechanism of infection caused by spores from pathogenic fungi.

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Vibrio fischeriDarR Directs Responses to D-Aspartate and Represents a Group of Similar LysR-Type Transcriptional Regulators

Journal of Bacteriology ◽

10.1128/jb.00773-17 ◽

2018 ◽

Vol 200 (15) ◽

Cited By ~ 2

Author(s):

Richard M. Jones ◽

David L. Popham ◽

Alicia L. Schmidt ◽

Ellen L. Neidle ◽

Eric V. Stabb

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Transcriptional Control ◽

Vibrio Fischeri ◽

Transcriptional Response ◽

Control Mechanisms ◽

Wild Type ◽

Acinetobacter Baylyi ◽

Transcriptional Responses ◽

Content Type

ABSTRACTMounting evidence suggests thatd-amino acids play previously underappreciated roles in diverse organisms. In bacteria, evend-amino acids that are absent from canonical peptidoglycan (PG) may act as growth substrates, as signals, or in other functions. Given these proposed roles and the ubiquity ofd-amino acids, the paucity of knownd-amino-acid-responsive transcriptional control mechanisms in bacteria suggests that such regulation awaits discovery. We found that DarR, a LysR-type transcriptional regulator (LTTR), activates transcription in response tod-Asp. Thed-Glu auxotrophy of aVibrio fischerimurI::Tn mutant was suppressed, with the wild-type PG structure maintained, by a point mutation indarR. ThisdarRmutation resulted in the overexpression of an adjacent operon encoding a putative aspartate racemase, RacD, which compensated for the loss of the glutamate racemase encoded bymurI. Using transcriptional reporters, we found that wild-type DarR activatedracDtranscription in response to exogenousd-Asp but not upon the addition ofl-Asp,l-Glu, ord-Glu. A DNA sequence typical of LTTR-binding sites was identified betweendarRand the divergently orientedracDoperon, and scrambling this sequence eliminated activation of the reporter in response tod-Asp. In several proteobacteria, genes encoding LTTRs similar to DarR are linked to genes with predicted roles ind- and/orl-Asp metabolism. To test the functional similarities in another bacterium,darRandracDmutants were also generated inAcinetobacter baylyi. InV. fischeriandA. baylyi, growth ond-Asp required the presence of bothdarRandracD. Our results suggest that multiple bacteria have the ability to sense and respond tod-Asp.IMPORTANCEd-Amino acids are prevalent in the environment and are generated by organisms from all domains of life. Although some biological roles ford-amino acids are understood, in other cases, their functions remain uncertain. Given the ubiquity ofd-amino acids, it seems likely that bacteria will initiate transcriptional responses to them. Elucidatingd-amino acid-responsive regulators along with the genes they control will help uncover bacterial uses ofd-amino acids. Here, we report the discovery of DarR, a novel LTTR inV. fischerithat mediates a transcriptional response to environmentald-Asp and underpins the catabolism ofd-Asp. DarR represents the founding member of a group of bacterial homologs that we hypothesize control aspects of aspartate metabolism in response tod-Asp and/or tod-Asp-containing peptides.

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Candida albicans Morphogenesis Is Not Required for Macrophage Interleukin 1β Production

mBio ◽

10.1128/mbio.00433-12 ◽

2012 ◽

Vol 4 (1) ◽

Cited By ~ 41

Author(s):

Melanie Wellington ◽

Kristy Koselny ◽

Damian J. Krysan

Keyword(s):

Transcription Factor ◽

Candida Albicans ◽

Interleukin 1Β ◽

Inflammasome Activation ◽

Wild Type ◽

Content Type ◽

Hypha Formation ◽

Physical Presence ◽

J774 Cells ◽

Low Levels

ABSTRACTThe interaction ofCandida albicanswith macrophages induces the production of interleukin 1β (IL-1β) through inflammasome activation in a process that is required for host survival.C. albicanshypha formation has been linked to IL-1β production, but the question of whether hyphae are sufficient to trigger IL-1β production has not been examined directly. To address this question, aC. albicanslibrary of 165 transcription factor deletion mutants was screened for strains with altered IL-1β production by lipopolysaccharide (LPS)-primed J774 cells, a murine macrophage-like cell line. Eight mutants with decreased and two mutants with increased IL-1β secretion were identified. In addition, 12 mutants with previously identified morphology deficits were found to induce IL-1β secretion to levels similar to those of the wild type. Examination of the morphology of both low and normal IL-1β-inducing mutants in macrophages revealed that two mutants (upc2Δ/upc2Δ andahr1Δ/Δ mutants) were indistinguishable from the wild type with respect to morphology yet induced low levels of IL-1β; conversely, thendt80Δ/Δ mutant was deficient for hypha formation but induced levels of IL-1β similar to those of the wild type. Transcription factor mutants deficient for IL-1β secretion also caused markedly lower levels of macrophage lysis. Similarly, the ability of a mutant to cause macrophage lysis was independent of its ability to form hyphae. Taken together, our observations indicate that the physical formation of hyphae is not sufficient to trigger IL-1β secretion or macrophage lysis and suggest that other mechanisms, such as pyroptosis, a caspase-1-dependent response to intracellular pathogens, may play a role in the interaction of macrophages withC. albicans.IMPORTANCEThe ability ofCandida albicansto transition from yeast to filamentous cells plays an important and complex role in pathogenesis. Recent results from a number of investigators indicate that the host responds to yeast and hyphalC. albicansdifferently. For example, aC. albicansmutant unable to form hyphae also fails to induce interleukin 1β (IL-1β) secretion from macrophages. We have identifiedC. albicanstranscription factor mutants that have decreased IL-1β secretion but retain the ability to form hyphae in response to macrophages. In addition, these mutants cause significantly less macrophage lysis. These observations indicate that the physical presence of the hyphal structure in the macrophage is not sufficient to trigger IL-1β secretion nor does it cause physical lysis of the cell. Our data indicate that characteristics of hyphae separate from its physical morphology are responsible for triggering the release of IL-1β release and causing macrophage lysis. Since these observations are inconsistent with some current models, alternative mechanisms for the interaction ofC. albicanswith macrophages must be considered.

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Activity of a Long-Acting Echinocandin (CD101) and Seven Comparator Antifungal Agents Tested against a Global Collection of Contemporary Invasive Fungal Isolates in the SENTRY 2014 Antifungal Surveillance Program

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02045-16 ◽

2017 ◽

Vol 61 (3) ◽

Cited By ~ 27

Author(s):

Michael A. Pfaller ◽

Shawn A. Messer ◽

Paul R. Rhomberg ◽

Mariana Castanheira

Keyword(s):

Antifungal Agents ◽

Fungal Infections ◽

The Other ◽

Surveillance Program ◽

Outpatient Basis ◽

Wild Type ◽

Content Type ◽

Fungal Isolates ◽

Fungal Organisms ◽

Long Acting

ABSTRACT The activity of CD101 and comparator antifungal agents against 606 invasive fungal isolates collected worldwide during 2014 was evaluated using the Clinical and Laboratory Standards Institute (CLSI) method. All Candida albicans (n = 251), Candida tropicalis (n = 51), Candida krusei (n = 16), and Candida dubliniensis (n = 11) isolates were inhibited by ≤0.12 μg/ml of CD101 and were susceptible or showed wild-type susceptibility to the other echinocandins tested. Five C. glabrata isolates (n = 100) displayed CD101 MIC values of 1 to 4 μg/ml, had elevated MICs of caspofungin (2 to >8 μg/ml), anidulafungin (2 to 4 μg/ml), and micafungin (2 to 4 μg/ml), and carried mutations on fks1 and fks2. Candida parapsilosis (n = 92) and Candida orthopsilosis (n = 10) displayed higher CD101 MIC values (ranges, 0.5 to 4 μg/ml and 0.12 to 2 μg/ml, respectively), and similar results were observed for the other echinocandins tested. Fluconazole resistance was noted among 11.0% of Candida glabrata isolates, 4.3% of C. parapsilosis isolates, and 2.0% of C. albicans and C. tropicalis isolates. The activity of CD101 against Aspergillus fumigatus (n = 56) was similar to that of micafungin and 2-fold greater than that of caspofungin but less than that of anidulafungin. These isolates had wild-type susceptibility to itraconazole, voriconazole, and posaconazole. The echinocandins had limited activity against Cryptococcus neoformans (n = 19). CD101 was as active as the other echinocandins against common fungal organisms recovered from patients with invasive fungal infections. The long half-life profile is very desirable for the prevention and treatment of serious fungal infections, especially in patients who can then be discharged from the hospital to complete antifungal therapy on an outpatient basis.

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