VT-1598 inhibits the in vitro growth of mucosal Candida strains and protects against fluconazole-susceptible and -resistant oral candidiasis in IL-17 signalling-deficient mice

Break, Timothy J.; Desai, Jigar V.; Healey, Kelley R.; Natarajan, Mukil; Ferré, Elise M. N.; Henderson, Christina M.; Zelazny, Adrian M.; Siebenlist, Ulrich; Yates, Christopher M.; Cohen, Oren J.; Schotzinger, Robert J.; Perlin, David S.; Garvey, Edward P.; Lionakis, Michail S.

doi:10.1093/jac/dky170

Cited by 24 publications

(23 citation statements)

References 22 publications

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“…In a randomized, double-blind phase 2 clinical trial evaluating oral VT-1161 in treating recurrent vulvovaginal candidiasis in 215 women, VT-1161 was found to be efficacious and safe compared to placebo with recurrence rates of between 0 and 7% through 48 weeks (24). VT-1598 has been effective in murine infection models with Candida, Coccidioides, and Cryptococcus species (23,37,38). However, reduced susceptibility has been observed to both VT-1161 and VT-1598 in clinical isolates of C. albicans, and this reduced in vitro susceptibility seems to be at least partly due to increased expression of the C. albicans ABC transporter Cdr1 (25,39).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, VT-1161 had previously shown to potently bind fungal CYP51 without binding the human equivalent of the fungal target enzyme, whereas VT-1598 boasts a broader spectrum of antifungal activity (20,22). Both agents have previously been shown to be effective against Candida strains, including azole-resistant strains, in vitro and in vivo (23)(24)(25)(26)(27).…”

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confidence: 99%

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Impact of the Major Candida glabrata Triazole Resistance Determinants on the Activity of the Novel Investigational Tetrazoles VT-1598 and VT-1161

Nishimoto

Whaley

Wiederhold

et al. 2019

Antimicrob Agents Chemother

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VT-1161 and VT-1598 are promising investigational tetrazole antifungals that have shown in vitro and in vivo activity against Candida and other fungi. Candida glabrata is a problematic opportunistic pathogen that is associated with high mortality in invasive infection, as well as both intrinsic and rapidly acquired antifungal resistance. The MICs of VT-1161 and VT-1598 were determined by CLSI methodology to evaluate their in vitro activities against clinical C. glabrata isolates and strains containing individual deletions of the zinc cluster transcription factor genes PDR1 and UPC2A as well as the efflux transporter genes CDR1, PDH1, and SNQ2. Overall, both tetrazoles demonstrated relative activities comparable to those of the tested triazole antifungals against clinical C. glabrata isolates (MIC range, 0.25 to 2 mg/liter and 0.5 to 2 μg/ml for VT-1161 and VT-1598, respectively). Deletion of the PDR1 gene in fluconazole-resistant matched clinical isolate SM3 abolished the decreased susceptibility phenotype completely for both VT-1161 and VT-1598, similarly to the triazoles. UPC2A deletion also increased susceptibility to both triazoles and tetrazoles but to a lesser extent than PDR1 deletion. Of the three major transporter genes regulated by Pdr1, CDR1 deletion resulted in the largest MIC reductions for all agents tested, while PDH1 and SNQ2 deletion individually impacted MICs very little. Overall, both VT-1161 and VT-1598 have comparable activities to those of the available triazoles, and decreased susceptibility to these tetrazoles in C. glabrata is driven by many of the same known resistance mechanisms.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Impact of the Major Candida glabrata Triazole Resistance Determinants on the Activity of the Novel Investigational Tetrazoles VT-1598 and VT-1161

Nishimoto

Whaley

Wiederhold

et al. 2019

Antimicrob Agents Chemother

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“…This topical therapeutic approach works best when it follows an induction treatment phase with a fungicidal parenteral drug such as an echinocandin to prevent recurrence of candidiasis rather than being effective as treatment of acute severe oral or esophageal candidiasis. Novel antifungal agents with remarkable in vitro and in vivo activity against azole‐susceptible and ‐resistant Candida strains require future investigation in APECED patients with severe azole‐resistant CMC, as does the Als3‐based fungal vaccine that boosts IL‐17‐mediated anti‐ Candida immunity and is the first fungal vaccine shown to display efficacy in humans . Routine screening for gastrointestinal cancers is a recommended practice for all patients.…”

Section: Management Of Apeced Patientsmentioning

confidence: 99%

“…Management of CMC is challenging in APECED patients because a substantial proportion of them develops azole-resistant Candida albicans and Candida glabrata strains, thus limiting long-term oral treatment options [139][140][141]. In our experience, the use of oral swish/swallow suspension of amphotericin B provides the best long-term preventive strategy in these patients with azole-resistance Candida strains.…”

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confidence: 93%

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

Constantine

Lionakis

2018

Immunological Reviews

122

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Summary: The discovery of the Autoimmune Regulator (AIRE) protein and the delineation of its critical contributions in the establishment of central immune tolerance has significantly expanded our understanding of the immunological mechanisms that protect from the development of autoimmune disease. The parallel identification and characterization of patient cohorts with the monogenic disorder Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED), which is typically caused by biallelic AIRE mutations, has underscored the critical contribution of AIRE in fungal immune surveillance at mucosal surfaces and in prevention of multiorgan autoimmunity in humans. In this review, we synthesize the current clinical, genetic, molecular and immunological knowledge derived from basic studies in Aire-deficient animals and from APECED patient cohorts. We also outline major advances and research endeavors that show promise for informing improved diagnostic and therapeutic approaches for patients with APECED.

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“…Pertinent to the present study, VT-1598 has also recently shown potent in vitro and in vivo antifungal activity against fluconazole-sensitive and -resistant Candida spp. isolated from chronic mucocutaneous candidiasis patients (36). Structurally, while the tetrazole moiety has lower affinity for interaction with the heme iron of CYP51, other structural modifications have made the drug more fungus specific.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Activities of the Novel Investigational Tetrazoles VT-1161 and VT-1598 Compared to the Triazole Antifungals against Azole-Resistant Strains and Clinical Isolates of Candida albicans

Nishimoto

Wiederhold

Flowers

et al. 2019

Antimicrob Agents Chemother

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The fungal Cyp51-specific inhibitors VT-1161 and VT-1598 have emerged as promising new therapies to combat fungal infections, including Candida spp. To evaluate their in vitro activities compared to other azoles, MICs were determined by Clinical and Laboratory Standards Institute (CLSI) method for VT-1161, VT-1598, fluconazole, voriconazole, itraconazole, and posaconazole against 68 C. albicans clinical isolates well characterized for azole resistance mechanisms and mutant strains representing individual azole resistance mechanisms. VT-1161 and VT-1598 demonstrated potent activity (geometric mean MICs Յ0.15 g/ml) against predominantly fluconazole-resistant (Ն8 g/ml) isolates. However, five of 68 isolates exhibited MICs greater than six dilutions (Ͼ2 g/ml) to both tetrazoles compared to fluconazolesusceptible isolates. Four of these isolates likewise exhibited high MICs beyond the upper limit of the assay for all triazoles tested. A premature stop codon in ERG3 likely explained the high-level resistance in one isolate. VT-1598 was effective against strains with hyperactive Tac1, Mrr1, and Upc2 transcription factors and against most ERG11 mutant strains. VT-1161 MICs were elevated compared to the control strain SC5314 for hyperactive Tac1 strains and two strains with Erg11 substitutions (Y132F and Y132F&K143R) but showed activity against hyperactive Mrr1 and Upc2 strains. While mutations affecting Erg3 activity appear to greatly reduce susceptibility to VT-1161 and VT-1598, the elevated MICs of both tetrazoles for four isolates could not be explained by known azole resistance mechanisms, suggesting the presence of undescribed resistance mechanisms to triazole-and tetrazole-based sterol demethylase inhibitors.

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VT-1598 inhibits the in vitro growth of mucosal Candida strains and protects against fluconazole-susceptible and -resistant oral candidiasis in IL-17 signalling-deficient mice

Cited by 24 publications

References 22 publications

Impact of the Major Candida glabrata Triazole Resistance Determinants on the Activity of the Novel Investigational Tetrazoles VT-1598 and VT-1161

Impact of the Major Candida glabrata Triazole Resistance Determinants on the Activity of the Novel Investigational Tetrazoles VT-1598 and VT-1161

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

In Vitro Activities of the Novel Investigational Tetrazoles VT-1161 and VT-1598 Compared to the Triazole Antifungals against Azole-Resistant Strains and Clinical Isolates of Candida albicans

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