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

Andrew T. Nishimoto, Nathan P. Wiederhold, Stephanie A. Flowers, Qing Zhang, Steven L. Kelly, Joachim Morschhäuser, Christopher M. Yates, William J. Hoekstra, Robert J. Schotzinger, Edward P. Garvey, Phillip Rogers

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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 0.15 g/ml) against predominantly fluconazole-resistant (8 g/ml) isolates. However, five of 68 isolates exhibited MICs greater than six dilutions (2 g/ml) to both tetrazoles compared to fluconazole-susceptible 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.

Original languageEnglish (US)
Article numbere00341-19
JournalAntimicrobial Agents and Chemotherapy
Volume63
Issue number6
DOIs
StatePublished - Jun 1 2019

Fingerprint

Tetrazoles
Azoles
Triazoles
Candida albicans
Fluconazole
Itraconazole
Mycoses
Nonsense Codon
Sterols
Candida
Transcription Factors
VT-1161
In Vitro Techniques
Mutation

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

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, Andrew T.; Wiederhold, Nathan P.; Flowers, Stephanie A.; Zhang, Qing; Kelly, Steven L.; Morschhäuser, Joachim; Yates, Christopher M.; Hoekstra, William J.; Schotzinger, Robert J.; Garvey, Edward P.; Rogers, Phillip.

In: Antimicrobial Agents and Chemotherapy, Vol. 63, No. 6, e00341-19, 01.06.2019.

Research output: Contribution to journalArticle

Nishimoto, Andrew T. ; Wiederhold, Nathan P. ; Flowers, Stephanie A. ; Zhang, Qing ; Kelly, Steven L. ; Morschhäuser, Joachim ; Yates, Christopher M. ; Hoekstra, William J. ; Schotzinger, Robert J. ; Garvey, Edward P. ; Rogers, Phillip. / 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. In: Antimicrobial Agents and Chemotherapy. 2019 ; Vol. 63, No. 6.
@article{19008c5f085d4022834c408ad494859b,
title = "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",
abstract = "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 0.15 g/ml) against predominantly fluconazole-resistant (8 g/ml) isolates. However, five of 68 isolates exhibited MICs greater than six dilutions (2 g/ml) to both tetrazoles compared to fluconazole-susceptible 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.",
author = "Nishimoto, {Andrew T.} and Wiederhold, {Nathan P.} and Flowers, {Stephanie A.} and Qing Zhang and Kelly, {Steven L.} and Joachim Morschh{\"a}user and Yates, {Christopher M.} and Hoekstra, {William J.} and Schotzinger, {Robert J.} and Garvey, {Edward P.} and Phillip Rogers",
year = "2019",
month = "6",
day = "1",
doi = "10.1128/AAC.00341-19",
language = "English (US)",
volume = "63",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "6",

}

TY - JOUR

T1 - 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

AU - Nishimoto, Andrew T.

AU - Wiederhold, Nathan P.

AU - Flowers, Stephanie A.

AU - Zhang, Qing

AU - Kelly, Steven L.

AU - Morschhäuser, Joachim

AU - Yates, Christopher M.

AU - Hoekstra, William J.

AU - Schotzinger, Robert J.

AU - Garvey, Edward P.

AU - Rogers, Phillip

PY - 2019/6/1

Y1 - 2019/6/1

N2 - 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 0.15 g/ml) against predominantly fluconazole-resistant (8 g/ml) isolates. However, five of 68 isolates exhibited MICs greater than six dilutions (2 g/ml) to both tetrazoles compared to fluconazole-susceptible 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.

AB - 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 0.15 g/ml) against predominantly fluconazole-resistant (8 g/ml) isolates. However, five of 68 isolates exhibited MICs greater than six dilutions (2 g/ml) to both tetrazoles compared to fluconazole-susceptible 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.

UR - http://www.scopus.com/inward/record.url?scp=85066432865&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85066432865&partnerID=8YFLogxK

U2 - 10.1128/AAC.00341-19

DO - 10.1128/AAC.00341-19

M3 - Article

VL - 63

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 6

M1 - e00341-19

ER -