scholarly journals Frequency offksMutations among Candida glabrata Isolates from a 10-Year Global Collection of Bloodstream Infection Isolates

2013 ◽  
Vol 58 (1) ◽  
pp. 577-580 ◽  
Author(s):  
Mariana Castanheira ◽  
Leah N. Woosley ◽  
Shawn A. Messer ◽  
Daniel J. Diekema ◽  
Ronald N. Jones ◽  
...  
Keyword(s):  
Bloodstream Infection ◽  
Hot Spots ◽  
Candida Glabrata ◽  
Wild Type ◽  
Glucan Synthase ◽  
Content Type

ABSTRACTAmong 119 echinocandin non-wild-type (non-WT)Candida glabratastrains from two global surveys, mutations infkshot spots (HSs) were detected in 28 (from 7 countries and 8 U.S. states): 24 strains (85.7%) had non-WT MICs for micafungin, 22 (78.6%) for anidulafungin, and 25 (89.3%) for caspofungin. The most common FKS substitutions among non-WT strains were at positions F659 (n= 7) and S663 (n= 7). Three isolates displaying WT MIC results had F625Y, L630I, and D632Y substitutions or non-HS mutations. Mutations that have been reported to decrease the echinocandin binding to the 1,3-β-d-glucan synthase were categorized as resistant by applying the new CLSI breakpoint criteria for all three echinocandins.

scholarly journals Activity of a Novel 1,3-Beta-D-Glucan Synthase Inhibitor, Ibrexafungerp (Formerly SCY-078), against Candida glabrata

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
M. Ghannoum ◽  
L. Long ◽  
N. Isham ◽  
C. Hager ◽  
R. Wilson ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Wild Type ◽  
Glucan Synthase ◽  
Content Type ◽  
Clinical Strains ◽  
Resistant Strains ◽  
Oral Availability ◽  
Synthase Inhibitor ◽  
Time Kill ◽  
Type Strains

ABSTRACT Ibrexafungerp (formerly SCY-078), a novel glucan synthase inhibitor with oral availability, was evaluated for activity against Candida glabrata. The susceptibility of clinical strains to ibrexafungerp was determined by microdilution and time-kill assays. The MIC range against wild-type strains was 1 to 2 μg/ml. Ibrexafungerp was also active against the majority of echinocandin-resistant strains. Time-kill studies showed 4- to 6-log-unit reductions in growth at 24 and 48 h with concentrations of 0.25 to 4 μg/ml.

scholarly journals Rate ofFKSMutations among Consecutive Candida Isolates Causing Bloodstream Infection

2015 ◽  
Vol 59 (12) ◽  
pp. 7465-7470 ◽  
Author(s):  
Ryan K. Shields ◽  
M. Hong Nguyen ◽  
Ellen G. Press ◽  
Richard Cumbie ◽  
Eileen Driscoll ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Bloodstream Infection ◽  
Hot Spots ◽  
Candida Glabrata ◽  
Susceptibility Testing ◽  
Mutation Rates ◽  
Broth Microdilution ◽  
Content Type ◽  
Clinical Breakpoints ◽  
Resistance Rates

ABSTRACTPreciseFKSmutation rates amongCandidaspecies are undefined because studies have not systematically screened consecutive, disease-causing isolates. The Sensititre YeastOne (SYO) assay measures echinocandin MICs againstCandidawith less variability than reference broth microdilution methods. However, clinical breakpoint MICs may overstate caspofungin nonsusceptibility compared to other agents. Our objectives were to determineCandidaFKSmutation rates by studying consecutive bloodstream isolates and to determine if discrepant susceptibility results were associated withFKSmutations.FKShot spots were sequenced in echinocandin-intermediate and -resistant isolates and those from patients with breakthrough candidemia or ≥3 days of prior echinocandin exposure. Overall, 453 isolates from 384 patients underwent susceptibility testing; 16% were echinocandin intermediate or resistant. Intermediate susceptibility rates were higher forCandida glabratathan for other species (P< 0.0001) and higher for caspofungin than for other agents (P< 0.0001). Resistance rates were similar between agents.FKSmutations were detected in 5% of sequenced isolates and 2% of isolates overall. Corresponding rates amongC. glabrataisolates were 8% and 4%, respectively. AmongCandida albicansisolates, rates were 5% and <1%, respectively. Mutations occurred exclusively with prior echinocandin exposure and were not detected in other species. Isolates with discrepant susceptibility results did not harborFKSmutations. Mutation rates among isolates resistant to ≥2, 1, and 0 agents were 75%, 13%, and 0%, respectively. In conclusion,FKSmutations were uncommon among non-C. glabrataspecies, even with prior echinocandin exposure. Discrepancies in echinocandin susceptibility by SYO testing were not driven by mutations and likely reflect imprecise caspofungin clinical breakpoints.

scholarly journals The Serratia marcescens Siderophore Serratiochelin Is Necessary for Full Virulence during Bloodstream Infection

2020 ◽  
Vol 88 (8) ◽  
Author(s):  
Danelle R. Weakland ◽  
Sara N. Smith ◽  
Bailey Bell ◽  
Ashootosh Tripathi ◽  
Harry L. T. Mobley
Keyword(s):  
Serratia Marcescens ◽  
Bloodstream Infection ◽  
Iron Acquisition ◽  
Gene Clusters ◽  
Clinical Isolates ◽  
Wild Type ◽  
Serratia Plymuthica ◽  
Content Type ◽  
Cas Assay ◽  
Essential Nutrient

ABSTRACT Serratia marcescens is a bacterium frequently found in the environment, but over the last several decades it has evolved into a concerning clinical pathogen, causing fatal bacteremia. To establish such infections, pathogens require specific nutrients; one very limited but essential nutrient is iron. We sought to characterize the iron acquisition systems in S. marcescens isolate UMH9, which was recovered from a clinical bloodstream infection. Using RNA sequencing (RNA-seq), we identified two predicted siderophore gene clusters (cbs and sch) that were regulated by iron. Mutants were constructed to delete each iron acquisition locus individually and in conjunction, generating both single and double mutants for the putative siderophore systems. Mutants lacking the sch gene cluster lost their iron-chelating ability as quantified by the chrome azurol S (CAS) assay, whereas the cbs mutant retained wild-type activity. Mass spectrometry-based analysis identified the chelating siderophore to be serratiochelin, a siderophore previously identified in Serratia plymuthica. Serratiochelin-producing mutants also displayed a decreased growth rate under iron-limited conditions created by dipyridyl added to LB medium. Additionally, mutants lacking serratiochelin were significantly outcompeted during cochallenge with wild-type UMH9 in the kidneys and spleen after inoculation via the tail vein in a bacteremia mouse model. This result was further confirmed by an independent challenge, suggesting that serratiochelin is required for full S. marcescens pathogenesis in the bloodstream. Nine other clinical isolates have at least 90% protein identity to the UMH9 serratiochelin system; therefore, our results are broadly applicable to emerging clinical isolates of S. marcescens causing bacteremia.

scholarly journals In Vitro Activity of Ibrexafungerp, a Novel Glucan Synthase Inhibitor against Candida glabrata Isolates with FKS Mutations

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Natalie S. Nunnally ◽  
Kizee A. Etienne ◽  
David Angulo ◽  
Shawn R. Lockhart ◽  
Elizabeth L. Berkow
Keyword(s):  
Candida Glabrata ◽  
Vitro Activity ◽  
Good Activity ◽  
In Vitro Activity ◽  
Broth Microdilution ◽  
Glucan Synthase ◽  
Content Type ◽  
Synthase Inhibitor

ABSTRACT Ibrexafungerp is a first-in-class glucan synthase inhibitor. In vitro activity was determined for 89 Candida glabrata isolates with molecularly identified FKS1 or FKS2 mutations conferring resistance to the echinocandins. All isolates were resistant to at least one echinocandin (i.e., anidulafungin, caspofungin, or micafungin) by broth microdilution. Results for ibrexafungerp were compared with those for each echinocandin. Ibrexafungerp had good activity against all echinocandin-resistant C. glabrata isolates.

scholarly journals Discovery of a Novel Class of Orally Active Antifungal β-1,3-d-Glucan Synthase Inhibitors

2011 ◽  
Vol 55 (11) ◽  
pp. 5099-5106 ◽  
Author(s):  
Scott S. Walker ◽  
Yiming Xu ◽  
Ilias Triantafyllou ◽  
Michelle F. Waldman ◽  
Cara Mendrick ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Candida Glabrata ◽  
Pharmacokinetic Data ◽  
Morphological Response ◽  
Glucan Synthase ◽  
Content Type ◽  
Safety Issues ◽  
Spontaneous Mutants ◽  
Orally Active

ABSTRACTThe echinocandins are a class of semisynthetic natural products that target β-1,3-glucan synthase (GS). Their proven clinical efficacy combined with minimal safety issues has made the echinocandins an important asset in the management of fungal infection in a variety of patient populations. However, the echinocandins are delivered only parenterally. A screen for antifungal bioactivities combined with mechanism-of-action studies identified a class of piperazinyl-pyridazinones that target GS. The compounds exhibitedin vitroactivity comparable, and in some cases superior, to that of the echinocandins. The compounds inhibit GSin vitro, and there was a strong correlation between enzyme inhibition andin vitroantifungal activity. In addition, like the echinocandins, the compounds caused a leakage of cytoplasmic contents from yeast and produced a morphological response in molds characteristic of GS inhibitors. Spontaneous mutants ofSaccharomyces cerevisiaewith reduced susceptibility to the piperazinyl-pyridazinones had substitutions inFKS1. The sites of these substitutions were distinct from those conferring resistance to echinocandins; likewise, echinocandin-resistant isolates remained susceptible to the test compounds. Finally, we present efficacy and pharmacokinetic data on an example of the piperazinyl-pyridazinone compounds that demonstrated efficacy in a murine model ofCandida glabratainfection.

scholarly journals Antifungal Activity of SCY-078 and Standard Antifungal Agents against 178 Clinical Isolates of Resistant and Susceptible Candida Species

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Wiley A. Schell ◽  
A. M. Jones ◽  
Katyna Borroto-Esoda ◽  
Barbara D. Alexander
Keyword(s):  
Candida Glabrata ◽  
Antifungal Agents ◽  
Candida Parapsilosis ◽  
Candida Krusei ◽  
Wild Type ◽  
Content Type ◽  
Clinical Resistance ◽  
Excellent Activity ◽  
Candida Lusitaniae

ABSTRACT SCY-078 in vitro activity was determined for 178 isolates of resistant or susceptible Candida albicans, Candida dubliniensis, Candida glabrata, Candida krusei, Candida lusitaniae, and Candida parapsilosis, including 44 Candida isolates with known genotypic (FKS1 or FKS2 mutations), phenotypic, or clinical resistance to echinocandins. Results were compared to those for anidulafungin, caspofungin, micafungin, fluconazole, and voriconazole. SCY-078 was shown to have excellent activity against both wild-type isolates and echinocandin- and azole-resistant isolates of Candida species.

scholarly journals Development of Caspofungin Resistance following Prolonged Therapy for Invasive Candidiasis Secondary to Candida glabrata Infection

2008 ◽  
Vol 52 (10) ◽  
pp. 3783-3785 ◽  
Author(s):  
George R. Thompson ◽  
Nathan P. Wiederhold ◽  
Ana C. Vallor ◽  
Nyria C. Villareal ◽  
James S. Lewis ◽  
...  
Keyword(s):  
Invasive Candidiasis ◽  
Hot Spots ◽  
Candida Glabrata ◽  
Glucan Synthase ◽  
Prolonged Therapy ◽  
Echinocandin Resistance

ABSTRACT We report a case of Candida glabrata invasive candidiasis that developed reduced susceptibility to caspofungin during prolonged therapy. Pre- and posttreatment isolates were confirmed to be isogenic, and sequencing of hot spots known to confer echinocandin resistance revealed an F659V substitution within the FKS2 region of the glucan synthase complex.

scholarly journals Facultative Sterol Uptake in an Ergosterol-Deficient Clinical Isolate of Candida glabrata Harboring a Missense Mutation inERG11and Exhibiting Cross-Resistance to Azoles and Amphotericin B

2012 ◽  
Vol 56 (8) ◽  
pp. 4223-4232 ◽  
Author(s):  
Claire M. Hull ◽  
Josie E. Parker ◽  
Oliver Bader ◽  
Michael Weig ◽  
Uwe Gross ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Clinical Isolate ◽  
Candida Glabrata ◽  
Sterol Composition ◽  
Single Amino Acid ◽  
Gas Chromatography Mass Spectrometry ◽  
Cross Resistance ◽  
Wild Type ◽  
Content Type ◽  
Sterol Uptake

ABSTRACTWe identified a clinical isolate ofCandida glabrata(CG156) exhibiting flocculent growth and cross-resistance to fluconazole (FLC), voriconazole (VRC), and amphotericin B (AMB), with MICs of >256, >256, and 32 μg ml−1, respectively. Sterol analysis using gas chromatography-mass spectrometry (GC-MS) revealed that CG156 was a sterol 14α-demethylase (Erg11p) mutant, wherein 14α-methylated intermediates (lanosterol was >80% of the total) were the only detectable sterols.ERG11sequencing indicated that CG156 harbored a single-amino-acid substitution (G315D) which nullified the function of native Erg11p. In heterologous expression studies using a doxycycline-regulatableSaccharomyces cerevisiae erg11strain, wild-typeC. glabrataErg11p fully complemented the function ofS. cerevisiaesterol 14α-demethylase, restoring growth and ergosterol synthesis in recombinant yeast; mutated CG156 Erg11p did not. CG156 was culturable using sterol-free, glucose-containing yeast minimal medium (glcYM). However, when grown on sterol-supplementedglcYM (with ergosta 7,22-dienol, ergosterol, cholestanol, cholesterol, Δ7-cholestenol, or desmosterol), CG156 cultures exhibited shorter lag phases, reached higher cell densities, and showed alterations in cellular sterol composition. Unlike comparator isolates (harboring wild-typeERG11) that became less sensitive to FLC and VRC when cultured on sterol-supplementedglcYM, facultative sterol uptake by CG156 did not affect its azole-resistant phenotype. Conversely, CG156 grown usingglcYM with ergosterol (or with ergosta 7,22-dienol) showed increased sensitivity to AMB; CG156 grown usingglcYM with cholesterol (or with cholestanol) became more resistant (MICs of 2 and >64 μg AMB ml−1, respectively). Our results provide insights into the consequences of sterol uptake and metabolism on growth and antifungal resistance inC. glabrata.

scholarly journals CgHog1-Mediated CgRds2 Phosphorylation Alters Glycerophospholipid Composition To Coordinate Osmotic Stress in Candida glabrata

2019 ◽  
Vol 85 (6) ◽  
Author(s):  
Chengjin Wu ◽  
Jiali Zhang ◽  
Guoxing Zhu ◽  
Rui Yao ◽  
Xiulai Chen ◽  
...  
Keyword(s):  
Cell Growth ◽  
Osmotic Stress ◽  
Cell Survival ◽  
Type Strain ◽  
Candida Glabrata ◽  
Wild Type Strain ◽  
Membrane Integrity ◽  
Wild Type ◽  
Content Type ◽  
Zinc Cluster

ABSTRACT Under stress conditions, Hog1 is required for cell survival through transiently phosphorylating downstream targets and reprogramming gene expression. Here, we report that Candida glabrata Hog1 (CgHog1) interacts with and phosphorylates CgRds2, a zinc cluster transcription factor, in response to osmotic stress. Additionally, we found that deletion of CgRDS2 led to decreases in cell growth and cell survival by 23.4% and 39.6%, respectively, at 1.5 M NaCl, compared with levels of the wild-type strain. This is attributed to significant downregulation of the expression levels of glycerophospholipid metabolism genes. As a result, the content of total glycerophospholipid decreased by 30.3%. Membrane integrity also decreased 47.6% in the Cgrds2Δ strain at 1.5 M NaCl. In contrast, overexpression of CgRDS2 increased the cell growth and cell survival by 10.2% and 6.3%, respectively, owing to a significant increase in the total glycerophospholipid content and increased membrane integrity by 27.2% and 12.1%, respectively, at 1.5 M NaCl, compared with levels for the wild-type strain. However, a strain in which the CgRDS2 gene encodes the replacement of Ser64 and Thr97 residues with alanines (Cgrds22A), harboring a CgRds2 protein that was not phosphorylated by CgHog1, failed to promote glycerophospholipid metabolism and membrane integrity at 1.5 M NaCl. Thus, the above results demonstrate that CgHog1-mediated CgRds2 phosphorylation enhanced glycerophospholipid composition and membrane integrity to resist osmotic stress in C. glabrata. IMPORTANCE This study explored the role of CgHog1-mediated CgRds2 phosphorylation in response to osmotic stress in Candida glabrata. CgHog1 interacts with and phosphorylates CgRds2, a zinc cluster transcription factor, under osmotic stress. Phosphorylated CgRds2 plays an important role in increasing glycerophospholipid composition and membrane integrity, thereby enhancing cell growth and survival.

scholarly journals Rapid Emergence of Echinocandin Resistance in Candida glabrata Resulting in Clinical and Microbiologic Failure

2013 ◽  
Vol 57 (9) ◽  
pp. 4559-4561 ◽  
Author(s):  
James S. Lewis ◽  
Nathan P. Wiederhold ◽  
Brian L. Wickes ◽  
Thomas F. Patterson ◽  
James H. Jorgensen
Keyword(s):  
Risk Factors ◽  
Hot Spots ◽  
Candida Glabrata ◽  
Content Type ◽  
Echinocandin Resistance ◽  
Initiation Of Therapy ◽  
Rapid Emergence

ABSTRACTWe report a case ofCandida glabratacandidemia that developed resistance to micafungin within 8 days of initiation of therapy in a patient without previous echinocandin exposure or other known risk factors for clinical or microbiological failure. Pre- and postresistant isolates were confirmed to be isogenic, and sequencing of hot spots known to confer echinocandin resistance revealed a phenylalanine deletion at codon 659 withinFKS2.

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