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

Jiménez‐Ortigosa, Cristina; Perez, Winder B.; Angulo, David; Borroto–Esoda, Katyna; Perlin, David S.

doi:10.1128/aac.00833-17

Cited by 70 publications

(53 citation statements)

References 12 publications

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“…As stated above, rezufungin can reportedly penetrate into deep tissue lesions better than micafungin [31] and exhibits a long half-life in pharmacokinetic studies [54,55]. An orally-active glucan synthase inhibitor, SCY-078 (Scynexis, Jersey City, NJ), exhibits activity against some otherwise-resistant FKS mutants [56], likely a result of a slightly different binding spot on the Fks protein [57].…”

Section: Micmentioning

confidence: 99%

Fungal resistance to echinocandins and the MDR phenomenon in Candida glabrata

Healey¹,

Perlin²

2018

Preprint

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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.

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Section: Micmentioning

confidence: 99%

Fungal resistance to echinocandins and the MDR phenomenon in Candida glabrata

Healey¹,

Perlin²

2018

Preprint

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“…Ibrexafungerp causes a decrease in (1→3)-β-D-glucan polymers and a weakening of the fungal cell wall [ 21 ]. Ibrexafungerp is structurally distinct from echinocandins and interacts differently with the target enzyme ( Figure 2 ) [ 22 ]. Although the binding site on (1→3)-β-D-glucan synthase for ibrexafungerp partially overlaps with a binding site for echinocandins, it appears to be nonidentical, resulting in a lower rate of resistance to ibrexafungerp [ 22 ].…”

Section: Ibrexafungerpmentioning

confidence: 99%

“…Ibrexafungerp is structurally distinct from echinocandins and interacts differently with the target enzyme ( Figure 2 ) [ 22 ]. Although the binding site on (1→3)-β-D-glucan synthase for ibrexafungerp partially overlaps with a binding site for echinocandins, it appears to be nonidentical, resulting in a lower rate of resistance to ibrexafungerp [ 22 ]. In in vitro studies, ibrexafungerp activity against wild-type and echinocandin-resistant strains of Candida spp.…”

Section: Ibrexafungerpmentioning

confidence: 99%

Ibrexafungerp: A Novel Oral Triterpenoid Antifungal in Development for the Treatment of Candida auris Infections

et al. 2020

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Candida auris is an emerging multidrug-resistant fungal pathogen reported worldwide. Infections due to C. auris are usually nosocomial and associated with high rates of fluconazole resistance and mortality. Echinocandins are utilized as the first-line treatment. However, echinocandins are only available intravenously and are associated with increasingly higher rates of resistance by C. auris. Thus, a need exists for novel treatments that demonstrate potent activity against C. auris. Ibrexafungerp is a first-in-class triterpenoid antifungal agent. Similar to echinocandins, ibrexafungerp inhibits (1→3)-β-D-glucan synthase, a key component of the fungal cell wall, resulting in fungicidal activity against Candida spp. Ibrexafungerp demonstrates broad in vitro activity against various Candida spp. including C. auris and C. auris isolates with fks mutations. Minimum inhibitory concentration (MIC50 and MIC90) values in >400 C. auris isolates were 0.5 μg/mL and 1.0 μg/mL, respectively. Clinical results were reported for two patients with invasive candidiasis or candidemia due to C. auris treated during the CARES (Candidiasis Caused by Candida Auris) trial, an ongoing open-label study. These patients experienced a complete response after treatment with ibrexafungerp. Thus, ibrexafungerp represents a promising new antifungal agent for treating C. auris infections.

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“…Importantly, SCY-078 appears to be active against echinocandin-resistant and azole-resistant Candida strains, including C. auris [ 111 , 112 , 113 ]. C. glabrata strains with acquired resistance to SCY-078 have already been described, harboring partially novel FKS mutations [ 114 ]. Results of a phase 2 trial evaluating SCY-078 as step-down treatment following micafungin are awaited (NCT02244606).…”

Section: Novel Drugs For Invasive Candidiasismentioning

confidence: 99%

Treatment of Invasive Candidiasis: A Narrative Review

Ben‐Ami

2018

JoF

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Invasive candidiasis occurs frequently in hospitalized patients, and is associated with high mortality rates due to delays in recognition and initiation of appropriate antifungals. Management of invasive candidiasis must take into account multiple host, pathogen, and drug-related factors, including the site of infection, host immune status, severity of sepsis, resistance and tolerance to antifungal agents, biofilm formation, and pharmacokinetic/pharmacodynamic considerations. Recent treatment directives have been shaped by the widespread introduction of echinocandins, highly potent and safe antifungals, into clinical use, as well as important changes in drug susceptibility patterns and the emergence of known and novel drug-resistant Candida species. Advances in molecular diagnostics have the potential to guide early targeted treatment of high-risk patients.

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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

Cited by 70 publications

References 12 publications

Fungal resistance to echinocandins and the MDR phenomenon in Candida glabrata

Fungal resistance to echinocandins and the MDR phenomenon in Candida glabrata

Ibrexafungerp: A Novel Oral Triterpenoid Antifungal in Development for the Treatment of Candida auris Infections

Treatment of Invasive Candidiasis: A Narrative Review

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