Background. Fluconazole (FLC) resistance is common in C. glabrata and echinocandins are often used as first-line therapy. Resistance to echinocandin therapy has been associated with FKS1 FKS2 gene alterations. Methods. We reviewed records of all patients bloodstream infection at Duke Hospital over the past decade (2001–2010) correlated treatment outcome minimum inhibitory concentration (MIC) results presence FKS mutations. For each isolate, MICs FLC (anidulafungin, caspofungin, micafungin)...

Abstract The fungal pathogen Candida glabrata has emerged as a major health threat since it readily acquires resistance to multiple drug classes, including triazoles and/or echinocandins. Thus far, cellular mechanisms promoting the emergence of classes have not been described in this organism. Here we demonstrate that mutator phenotype caused by mismatch repair defect is prevalent C. clinical isolates. Strains carrying alterations gene MSH2 exhibit higher propensity breakthrough antifungal...

ABSTRACT MK-3118 is as an orally active new antifungal in the early stage of clinical development that inhibits biosynthesis β-(1,3)-glucan. We evaluated vitro activity this compound against wild-type and echinocandin-resistant (ER) isolates containing mutations FKS gene(s) Candida spp. Aspergillus demonstrated enhanced efficacy for most C. albicans glabrata ER relative to caspofungin, with decreased MICs half-maximal inhibitory concentrations (IC 50 s).

Expanding echinocandin use to prevent or treat invasive fungal infections has led an increase in the number of breakthrough due resistant Candida species. Although it is uncommon, resistance well documented for albicans, which among most prevalent bloodstream organisms. A better understanding needed assess cellular factors that promote tolerance and predispose infecting cells clinical breakthrough. We previously showed some mutants were adapted growth presence toxic sorbose loss one...

SCY-078 is an orally active antifungal whose target the β-(1,3)-d-glucan synthase (GS). We evaluated spontaneous emergence of SCY-078-resistant Candida glabrata isolates following drug exposure in vitro Resistant were analyzed using broth microdilution methodology and FKS sequencing. The kinetic inhibition parameter IC50 (50% inhibitory concentration) was also determined from GS complexes. spectrum resistance mutations found suggested a partially overlapping but independent binding site for...

CD101 is a novel echinocandin drug being developed to treat severe fungal infections including invasive candidiasis. We have performed series of studies evaluate the antifungal properties against both echinocandin-susceptible and -resistant Candida strains. Antifungal susceptibility testing on collection 95 strains 30 caspofungin-resistant isolates containing fks mutations demonstrated comparable potency relative micafungin (MCF) across different species. Comparable kinetic inhibition glucan...

We have identified the first case of an fks1 hot spot 1 point mutation causing echinocandin resistance in a clinical Aspergillus fumigatus isolate recovered from chronic pulmonary aspergillosis patient with aspergilloma who failed azole and polyene therapy subsequently micafungin treatment.

We identified a case of breakthrough candidemia in 25-year-old patient receiving micafungin prophylaxis (50 mg/day). Five Candida glabrata isolates were obtained from blood cultures and classified as multidrug-resistant isolates, since all them exhibited high MICs for echinocandin azole drugs. A mutation (S663F) hot spot 1 the FKS2 gene was found five isolates. This yielded 1,3-β-D-glucan synthase enzyme with highly reduced sensitivities to

Azole-resistant aspergillosis in high-risk patients with hematological malignancy or hematopoietic stem cell transplantation (HSCT) is a cause of concern.We examined changes over time triazole minimum inhibitory concentrations (MICs) 290 sequential Aspergillus isolates recovered from respiratory sources during 1999-2002 (before introduction the Aspergillus-potent triazoles voriconazole and posaconazole) 2003-2015 at MD Anderson Cancer Center. We also tested for polymorphisms ergosterol...

Aspergillus fumigatus has two chitin synthases (CSMA and CSMB) with a myosin motor-like domain (MMD) arranged in head-to-head configuration. To understand the function of these synthases, single double csm mutant strains were constructed analyzed. Although there was slight reduction mycelial growth mutants, total synthase activity cell wall content similar mycelium all mutants parental strain. In conidia, ΔcsmA strain less than half amount found contrast, ΔcsmB and, unexpectedly, ΔcsmA/ΔcsmB...

Candida auris is an emerging multidrug-resistant yeast that can cause serious invasive infections. The accurate and rapid assessment of antifungal resistance important for effective patient management.

Aspergillus fumigatus is a leading cause of invasive fungal infections. Resistance to first-line triazole antifungals has led therapy with echinocandin drugs. Recently, we identified several high-minimum-effective-concentration (MEC) A. clinical isolates from patients failing therapy. Echinocandin resistance known arise amino acid substitutions in β-(1,3)-d-glucan synthase encoded by the fks1 gene. Yet these did not contain mutations fks1, indicating an undefined mechanism. To explore this...

Clinical echinocandin resistance among Candida glabrata strains is increasing, especially in the United States. Antifungal susceptibility testing considered mandatory to guide therapeutic decisions. However, these methodologies are not routinely performed hospital setting due their complexity and time needed obtain reliable results. Echinocandin failure C. linked exclusively Fks1p Fks2p amino acid substitutions, detection of such substitutions would serve as a surrogate marker identify...

APX001 is a first-in-class, intravenous and orally available, broad-spectrum antifungal agent in clinical development for the treatment of life-threatening invasive fungal infections. The half-life APX001A, active moiety APX001, significantly shorter mice than humans (1.4 to 2.75 h versus 2 2.5 days humans), making exploration efficacy mouse models difficult. After pretreatment with 1-aminobenzotriazole (ABT), nonspecific cytochrome P450 inhibitor, greatly increased plasma APX001A exposure...

Fungal infections cause significant mortality and morbidity worldwide, the limited existing antifungal reservoir is further weakened by emergence of strains resistant to echinocandins, a first line therapy. Candida glabrata an opportunistic fungal pathogen that rapidly develops mutations in echinocandin drug target β-1,3-glucan synthase (GS), which are associated with resistance clinical failure. Although echinocandins considered fungicidal sp., subset C. cells survive exposure, forming...

Fungal plasma membrane proteins have long been recognized as targets for the development of antifungal agents. Despite recent progress in experimental approaches and computational structural predictions, our knowledge dynamics spatial distribution these context their native lipid environment remains limited. By applying cryo-electron tomography (cryoET) subtomogram analysis, we aim to characterize characteristics present Candida glabrata membranes. This study has resulted identification...

A rapid molecular-based assay for the detection of Candida albicans FKS1 gene mutations responsible resistance to echinocandin drugs was designed and evaluated. The consisted a multiplexed PCR set 5 tubes able detect most commonly described mechanism, including hot spot 1 2 mutations. performance specificity evaluated using double-blinded panel 50 C. strains. showed sensitivity 96% all homozygous mutants included in collection strains, demonstrating that it is robust, quick, labor-saving...

ABSTRACT Candida kefyr is an increasingly reported pathogen in patients with hematologic malignancies. We studied a series of bloodstream isolates that exhibited reduced echinocandin susceptibilities (RES). Clinical and surveillance were tested for to all three echinocandins, those displaying RES one or more echinocandins selected molecular biochemical studies. The analyzed genetic similarities, subset was mutations the target gene FKS1 glucan synthase sensitivities using methods. typing did...

Background. Candida tropicalis is a virulent fungal pathogen for which echinocandins are the primary therapy. Emergence of resistance to C. carries potentially ominous therapeutic implications. Methods. We describe herein two patients with breakthrough fungemia during echinocandin therapy, characterize their molecular mechanism resistance, and systematically review 13 previously reported cases echinocandin-resistant bloodstream infections (BSIs) other diseases. Results. Among these 15...

Fungal infections are common complications of respiratory viral and associated with the increased need for intensive care elevated mortality. Data regarding microbiological molecular characteristics such in COVID-19 patients scarce. Here, we performed a comprehensive analysis, including species identification, antifungal susceptibility testing, resistance determinants typing, retrospective clinical data review, fungal isolates recovered from 19 patients, who were hospitalized at Hackensack...

Journal Article Elucidating the 3D Structure of β-(1,3)-glucan Synthase from Candida glabrata by Subtomogram Averaging Get access Jennifer Jiang, Jiang Institute for Quantitative Biomedicine, Rutgers, The State University New Jersey, Piscataway, NJ, United StatesDepartment Cell Biology and Neuroscience, School Arts Sciences, States Search other works this author on: Oxford Academic Google Scholar Cristina Jiménez-Ortigosa, Jiménez-Ortigosa Hackensack Meridian Health-Center Discovery...

We analyzed a cohort of Trichosporon asahii strains with different MICs fluconazole and voriconazole evaluated the presence ERG11 mutations. mutation conferring an amino acid change was found its resistance potential by cloning into Saccharomyces cerevisiae susceptible host strain. Transformants were not resistant to either nor voriconazole. Our results suggest that variants exist among T. isolates, but are responsible for phenotypes.

The aim of this study is to describe the clinical manifestations, molecular mechanisms, and treatment outcomes patients with echinocandin-resistant Candida tropicalis (C. tropicalis) bloodstream infections (BSI). A PubMed search was conducted using terms related C. BSI echinocandin resistance. Two previously unreported cases from our institution diagnosed tropicalisBSI that developed resistance echinocandins were also included. Demographics, comorbidities, treatment, outcomes, mechanisms...