scholarly journals De Novo Acquisition of Resistance to SCY-078 in Candida glabrata Involves FKS Mutations That both Overlap and Are Distinct from Those Conferring Echinocandin Resistance

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Cristina Jiménez-Ortigosa ◽  
Winder B. Perez ◽  
David Angulo ◽  
Katyna Borroto-Esoda ◽  
David S. Perlin
Keyword(s):  
Candida Glabrata ◽  
Drug Exposure ◽  
Inhibitory Concentration ◽  
De Novo ◽  
Resistance Mutations ◽  
Content Type ◽  
Kinetic Inhibition ◽  
Echinocandin Resistance ◽  
Orally Active

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

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 In Vitro Exposure to Increasing Micafungin Concentrations Easily Promotes Echinocandin Resistance in Candida glabrata Isolates

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
María Ángeles Bordallo-Cardona ◽  
Pilar Escribano ◽  
Elia Gómez G. de la Pedrosa ◽  
Laura Judith Marcos-Zambrano ◽  
Rafael Cantón ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Content Type ◽  
Inhibition Of Growth ◽  
Direct Exposure ◽  
In Vitro Exposure ◽  
Echinocandin Resistance

ABSTRACT We assessed the in vitro susceptibility of five echinocandin-susceptible Candida glabrata isolates after exposure to micafungin. The direct exposure to plates at different micafungin concentrations resulted in the inhibition of growth at 0.062 μg/ml. The progressive exposure was performed on plates using 0.031 μg/ml of micafungin and sequential propagation on plates containing the next 2-fold concentration; the MICs of micafungin and anidulafungin increased sequentially, and all the isolates became echinocandin resistant, showing fks2 mutations.

scholarly journals The Gastrointestinal Tract Is a Major Source of Echinocandin Drug Resistance in a Murine Model of Candida glabrata Colonization and Systemic Dissemination

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Kelley R. Healey ◽  
Yoji Nagasaki ◽  
Matthew Zimmerman ◽  
Milena Kordalewska ◽  
Steven Park ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Human Microbiome ◽  
Systemic Infection ◽  
Resistance Mutations ◽  
Content Type ◽  
Systemic Dissemination ◽  
Colonization Model ◽  
Echinocandin Resistance ◽  
Synthase Inhibitor ◽  
Resistance Rates

ABSTRACT Candida species are a part of the human microbiome and can cause systemic infection upon immune suppression. Candida glabrata infections are increasing and have greater rates of antifungal resistance than other species. Here, we present a C. glabrata gastrointestinal (GI) colonization model to explore whether colonized yeast exposed to caspofungin, an echinocandin antifungal, develop characteristic resistance mutations and, upon immunosuppression, breakthrough causing systemic infection. Daily therapeutic dosing (5 mg/kg of body weight) of caspofungin resulted in no reduction in fecal burdens, organ breakthrough rates similar to control groups, and resistance rates (0 to 10%) similar to those reported clinically. Treatment with 20 mg/kg caspofungin initially reduced burdens, but a rebound following 5 to 9 days of treatment was accompanied by high levels of resistance (FKS1/FKS2 mutants). Although breakthrough rates decreased in this group, the same FKS mutants were recovered from organs. In an attempt to negate drug tolerance that is critical for resistance development, we cotreated mice with daily caspofungin and the chitin synthase inhibitor nikkomycin Z. The largest reduction (3 log) in GI burdens was obtained within 3 to 5 days of 20 mg/kg caspofungin plus nikkomycin treatment. Yet, echinocandin resistance, characterized by a novel Fks1-L630R substitution, was identified following 5 to 7 days of treatment. Therapeutic caspofungin plus nikkomycin treatment left GI burdens unchanged but significantly reduced organ breakthrough rates (20%; P < 0.05). Single-dose pharmacokinetics demonstrated low levels of drug penetration into the GI lumen posttreatment with caspofungin. Overall, we show that C. glabrata echinocandin resistance can arise within the GI tract and that resistant mutants can readily disseminate upon immunosuppression.

scholarly journals Rapid Detection ofFKS-Associated Echinocandin Resistance in Candida glabrata

2016 ◽  
Vol 60 (11) ◽  
pp. 6573-6577 ◽  
Author(s):  
Yanan Zhao ◽  
Yoji Nagasaki ◽  
Milena Kordalewska ◽  
Ellen G. Press ◽  
Ryan K. Shields ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Molecular Beacon ◽  
Rapid Identification ◽  
Molecular Diagnostic ◽  
Wild Type ◽  
Asymmetric Pcr ◽  
Content Type ◽  
Allele Specific ◽  
Echinocandin Resistance

ABSTRACTA novel and highly accurate diagnostic assay platform was established for rapid identification ofFKSmutations associated with echinocandin resistance inCandida glabrata. The assay platform uses allele-specific molecular beacon and DNA melt analysis following asymmetric PCR. A dual assay forFKS1andFKS2was developed to identify within 3 h the most common and clinically relevant resistance-associated mutations, including 8FKS1HS1 (wild type [WT], S629P, F625S, D632Y, D632E [T1896G], D632E [T1896A], I634V, and F625F) and 7FKS2HS1 (WT, F659del, F659S, F659V, F659L, S663P, and S663F) genotypes. A blinded panel of 188C. glabrataclinical isolates was tested by both assays. The molecular diagnostic results from the dual assay were 100% concordant with data obtained from DNA sequencing. This platform has the potential to overcome the deficiencies of existingin vitrosusceptibility-based assays to identify echinocandin-resistantC. glabrataand holds promise as a surrogate diagnostic method to better direct echinocandin therapy.

scholarly journals Fungal resistance to echinocandins and the MDR phenomenon in Candida glabrata

2018 ◽  
Author(s):  
Kelley Healey ◽  
David S Perlin
Keyword(s):  
Candida Glabrata ◽  
Drug Exposure ◽  
Target Genes ◽  
Genetic Resistance ◽  
Fungal Resistance ◽  
Drug Pressure ◽  
Adaptive Resistance ◽  
Echinocandin Resistance

Candida glabrata has thoroughly adapted to successfully colonize human mucosal membranes and survive in vivo pressures prior to and during antifungal treatment. Out of all the medically relevant Candida species, C. glabrata has emerged as a leading cause of azole, echinocandin, and multidrug (MDR: azole + echinocandin) adaptive resistance. Neither mechanism of resistance is intrinsic to C. glabrata, since stable genetic resistance depends on mutation of drug target genes, FKS1 and FKS2 (echinocandin resistance), and a transcription factor, PDR1, which controls expression of major drug transporters, such as CDR1 (azole resistance). However, another hallmark of C. glabrata is the ability to withstand drug pressure both in vitro and in vivo prior to stable ‘genetic escape’. Additionally, these resistance events can arise within individual patients, which underscores the importance of understanding how this fungus is adapting to its environment and to drug exposure in vivo. Here, we explore the evolution of echinocandin resistance as a multistep model that includes general cell stress, drug adaptation (tolerance), and genetic escape. The extensive genetic diversity reported in C. glabrata will be highlighted.

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 Nitro/Nitrosyl-Ruthenium Complexes Are Potent and Selective Anti-Trypanosoma cruzi Agents Causing Autophagy and Necrotic Parasite Death

2014 ◽  
Vol 58 (10) ◽  
pp. 6044-6055 ◽  
Author(s):  
Tanira M. Bastos ◽  
Marília I. F. Barbosa ◽  
Monize M. da Silva ◽  
José W. da C. Júnior ◽  
Cássio S. Meira ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Inhibitory Concentration ◽  
Content Type ◽  
X Ray ◽  
X Ray Crystallography ◽  
Ruthenium Nitrosyl ◽  
Index Analysis ◽  
Antiparasitic Drug ◽  
Drug Complex

ABSTRACTcis-[RuCl(NO2)(dppb)(5,5′-mebipy)] (complex 1),cis-[Ru(NO2)2(dppb)(5,5′-mebipy)] (complex 2),ct-[RuCl(NO)(dppb)(5,5′-mebipy)](PF6)2(complex 3), andcc-[RuCl(NO)(dppb)(5,5′-mebipy)](PF6)2(complex 4), where 5,5′-mebipy is 5,5′-dimethyl-2,2′-bipyridine and dppb is 1,4-bis(diphenylphosphino)butane, were synthesized and characterized. The structure of complex 2 was determined by X-ray crystallography. These complexes exhibited a higher anti-Trypanosoma cruziactivity than benznidazole, the current antiparasitic drug. Complex 3 was the most potent, displaying a 50% effective concentration (EC50) of 2.1 ± 0.6 μM against trypomastigotes and a 50% inhibitory concentration (IC50) of 1.3 ± 0.2 μM against amastigotes, while it displayed a 50% cytotoxic concentration (CC50) of 51.4 ± 0.2 μM in macrophages. It was observed that the nitrosyl complex 3, but not its analog lacking the nitrosyl group, releases nitric oxide into parasite cells. This release has a diminished effect on the trypanosomal protease cruzain but induces substantial parasite autophagy, which is followed by a series of irreversible morphological impairments to the parasites and finally results in cell death by necrosis. In infected mice, orally administered complex 3 (five times at a dose of 75 μmol/kg of body weight) reduced blood parasitemia and increased the survival rate of the mice. Combination index analysis of complex 3 indicated that itsin vitroactivity against trypomastigotes is synergic with benznidazole. In addition, drug combination enhanced efficacy in infected mice, suggesting that ruthenium-nitrosyl complexes are potential constituents for drug combinations.

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 In VitroActivity of Omadacycline againstChlamydia pneumoniae

2018 ◽  
Vol 63 (2) ◽  
pp. e01907-18 ◽  
Author(s):  
Stephan A. Kohlhoff ◽  
Natalia Huerta ◽  
Margaret R. Hammerschlag
Keyword(s):  
Minimum Inhibitory Concentration ◽  
Chlamydia Pneumoniae ◽  
Inhibitory Concentration ◽  
Content Type

ABSTRACTThein vitroactivities of omadacycline, azithromycin, doxycycline, moxifloxacin, and levofloxacin were tested against 15 isolates ofChlamydia pneumoniae. The minimum inhibitory concentration at which 90% of the isolates ofC. pneumoniaewere inhibited by omadacycline was 0.25 μg/ml (range, 0.03 to 0.5 μg/ml).

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