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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 Kelly Orcid Logo, Joachim Morschhäuser, Christopher M. Yates, William J. Hoekstra, Robert J. Schotzinger, Edward P. Garvey, P. David Rogers

Antimicrobial Agents and Chemotherapy, Volume: 63, Issue: 6

Swansea University Author: Steven Kelly Orcid Logo

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DOI (Published version): 10.1128/aac.00341-19

Abstract

The fungal Cyp51-specific inhibitors VT-1161 and VT-1598 have emerged as promising new 24 therapies to combat fungal infections, including Candida spp. To evaluate the in vitro activity of 25 these compounds in comparison to other available azoles, minimum inhibitory concentrations 26 (MICs) were de...

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Published in: Antimicrobial Agents and Chemotherapy
ISSN: 0066-4804 1098-6596
Published: American Society for Microbiology 2019
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URI: https://cronfa.swan.ac.uk/Record/cronfa49785
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VT-1161 29 and VT-1598 demonstrated potent activity (geometric mean MICs &#x2264;0.15 &#x3BC;g/mL) against 30 predominantly fluconazole-resistant isolates. However, five of 68 isolates exhibited MICs 31 greater than six dilutions (&amp;#62;2 &#x3BC;g/mL) to both tetrazoles compared to fluconazole-susceptible 32 isolates. Four of these isolates likewise exhibited high MICs beyond the upper limit for all 33 triazoles tested. A premature stop codon in ERG3 likely explained the high-level resistance in 34 one isolate. VT-1598 was effective against strains with hyperactive Tac1, Mrr1, and Upc2 35 transcription factors and against most ERG11 mutant strains. VT-1161 MICs were elevated for 36 hyperactive Tac1 strains and two strains with Erg11 substitutions (Y132F and Y132F&amp;K143R), 37 but showed activity against strains with hyperactive forms of Mrr1 and Upc2. VT-1161 had 38 elevated MICs against a minority of clinical isolates that were more susceptible to itraconazole 39 (3), voriconazole (1), or posaconazole (5). While mutations affecting Erg3 activity appear to 40 greatly reduce susceptibility to VT-1161 and VT-1598, the elevated MICs of both tetrazoles for 41 four isolates could not be explained by known azole resistance mechanisms, suggesting the 42 presence of undescribed resistance mechanisms to triazole- and tetrazole-based sterol 43 demethylase inhibitors.</abstract><type>Journal Article</type><journal>Antimicrobial Agents and Chemotherapy</journal><volume>63</volume><journalNumber>6</journalNumber><paginationStart/><paginationEnd/><publisher>American Society for Microbiology</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0066-4804</issnPrint><issnElectronic>1098-6596</issnElectronic><keywords/><publishedDay>1</publishedDay><publishedMonth>6</publishedMonth><publishedYear>2019</publishedYear><publishedDate>2019-06-01</publishedDate><doi>10.1128/aac.00341-19</doi><url>http://dx.doi.org/10.1128/aac.00341-19</url><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm/><lastEdited>2021-10-26T16:29:13.0558337</lastEdited><Created>2019-03-28T10:33:26.5042423</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Andrew T.</firstname><surname>Nishimoto</surname><order>1</order></author><author><firstname>Nathan P.</firstname><surname>Wiederhold</surname><order>2</order></author><author><firstname>Stephanie A.</firstname><surname>Flowers</surname><order>3</order></author><author><firstname>Qing</firstname><surname>Zhang</surname><order>4</order></author><author><firstname>Steven</firstname><surname>Kelly</surname><orcid>0000-0001-7991-5040</orcid><order>5</order></author><author><firstname>Joachim</firstname><surname>Morschh&#xE4;user</surname><order>6</order></author><author><firstname>Christopher M.</firstname><surname>Yates</surname><order>7</order></author><author><firstname>William J.</firstname><surname>Hoekstra</surname><order>8</order></author><author><firstname>Robert J.</firstname><surname>Schotzinger</surname><order>9</order></author><author><firstname>Edward P.</firstname><surname>Garvey</surname><order>10</order></author><author><firstname>P. David</firstname><surname>Rogers</surname><order>11</order></author></authors><documents><document><filename>0049785-11042019092721.pdf</filename><originalFilename>49785.pdf</originalFilename><uploaded>2019-04-11T09:27:21.7570000</uploaded><type>Output</type><contentLength>908824</contentLength><contentType>application/pdf</contentType><version>Accepted Manuscript</version><cronfaStatus>true</cronfaStatus><embargoDate>2019-09-25T00:00:00.0000000</embargoDate><copyrightCorrect>true</copyrightCorrect><language>eng</language></document></documents><OutputDurs/></rfc1807>
spelling 2021-10-26T16:29:13.0558337 v2 49785 2019-03-28 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 b17cebaf09b4d737b9378a3581e3de93 0000-0001-7991-5040 Steven Kelly Steven Kelly true false 2019-03-28 BMS The fungal Cyp51-specific inhibitors VT-1161 and VT-1598 have emerged as promising new 24 therapies to combat fungal infections, including Candida spp. To evaluate the in vitro activity of 25 these compounds in comparison to other available azoles, minimum inhibitory concentrations 26 (MICs) were determined for VT-1161, VT-1598, fluconazole, voriconazole, itraconazole, and 27 posaconazole against 68 C. albicans clinical isolates well-characterized for azole resistance 28 mechanisms and mutant strains representing individual azole resistance mechanisms. VT-1161 29 and VT-1598 demonstrated potent activity (geometric mean MICs ≤0.15 μg/mL) against 30 predominantly fluconazole-resistant isolates. However, five of 68 isolates exhibited MICs 31 greater than six dilutions (&#62;2 μg/mL) to both tetrazoles compared to fluconazole-susceptible 32 isolates. Four of these isolates likewise exhibited high MICs beyond the upper limit for all 33 triazoles tested. A premature stop codon in ERG3 likely explained the high-level resistance in 34 one isolate. VT-1598 was effective against strains with hyperactive Tac1, Mrr1, and Upc2 35 transcription factors and against most ERG11 mutant strains. VT-1161 MICs were elevated for 36 hyperactive Tac1 strains and two strains with Erg11 substitutions (Y132F and Y132F&K143R), 37 but showed activity against strains with hyperactive forms of Mrr1 and Upc2. VT-1161 had 38 elevated MICs against a minority of clinical isolates that were more susceptible to itraconazole 39 (3), voriconazole (1), or posaconazole (5). While mutations affecting Erg3 activity appear to 40 greatly reduce susceptibility to VT-1161 and VT-1598, the elevated MICs of both tetrazoles for 41 four isolates could not be explained by known azole resistance mechanisms, suggesting the 42 presence of undescribed resistance mechanisms to triazole- and tetrazole-based sterol 43 demethylase inhibitors. Journal Article Antimicrobial Agents and Chemotherapy 63 6 American Society for Microbiology 0066-4804 1098-6596 1 6 2019 2019-06-01 10.1128/aac.00341-19 http://dx.doi.org/10.1128/aac.00341-19 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2021-10-26T16:29:13.0558337 2019-03-28T10:33:26.5042423 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Andrew T. Nishimoto 1 Nathan P. Wiederhold 2 Stephanie A. Flowers 3 Qing Zhang 4 Steven Kelly 0000-0001-7991-5040 5 Joachim Morschhäuser 6 Christopher M. Yates 7 William J. Hoekstra 8 Robert J. Schotzinger 9 Edward P. Garvey 10 P. David Rogers 11 0049785-11042019092721.pdf 49785.pdf 2019-04-11T09:27:21.7570000 Output 908824 application/pdf Accepted Manuscript true 2019-09-25T00:00:00.0000000 true eng
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
spellingShingle 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
Steven Kelly
title_short 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_sort 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
author_id_str_mv b17cebaf09b4d737b9378a3581e3de93
author_id_fullname_str_mv b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly
author Steven Kelly
author2 Andrew T. Nishimoto
Nathan P. Wiederhold
Stephanie A. Flowers
Qing Zhang
Steven Kelly
Joachim Morschhäuser
Christopher M. Yates
William J. Hoekstra
Robert J. Schotzinger
Edward P. Garvey
P. David Rogers
format Journal article
container_title Antimicrobial Agents and Chemotherapy
container_volume 63
container_issue 6
publishDate 2019
institution Swansea University
issn 0066-4804
1098-6596
doi_str_mv 10.1128/aac.00341-19
publisher American Society for Microbiology
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
url http://dx.doi.org/10.1128/aac.00341-19
document_store_str 1
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description The fungal Cyp51-specific inhibitors VT-1161 and VT-1598 have emerged as promising new 24 therapies to combat fungal infections, including Candida spp. To evaluate the in vitro activity of 25 these compounds in comparison to other available azoles, minimum inhibitory concentrations 26 (MICs) were determined for VT-1161, VT-1598, fluconazole, voriconazole, itraconazole, and 27 posaconazole against 68 C. albicans clinical isolates well-characterized for azole resistance 28 mechanisms and mutant strains representing individual azole resistance mechanisms. VT-1161 29 and VT-1598 demonstrated potent activity (geometric mean MICs ≤0.15 μg/mL) against 30 predominantly fluconazole-resistant isolates. However, five of 68 isolates exhibited MICs 31 greater than six dilutions (&#62;2 μg/mL) to both tetrazoles compared to fluconazole-susceptible 32 isolates. Four of these isolates likewise exhibited high MICs beyond the upper limit for all 33 triazoles tested. A premature stop codon in ERG3 likely explained the high-level resistance in 34 one isolate. VT-1598 was effective against strains with hyperactive Tac1, Mrr1, and Upc2 35 transcription factors and against most ERG11 mutant strains. VT-1161 MICs were elevated for 36 hyperactive Tac1 strains and two strains with Erg11 substitutions (Y132F and Y132F&K143R), 37 but showed activity against strains with hyperactive forms of Mrr1 and Upc2. VT-1161 had 38 elevated MICs against a minority of clinical isolates that were more susceptible to itraconazole 39 (3), voriconazole (1), or posaconazole (5). While mutations affecting Erg3 activity appear to 40 greatly reduce susceptibility to VT-1161 and VT-1598, the elevated MICs of both tetrazoles for 41 four isolates could not be explained by known azole resistance mechanisms, suggesting the 42 presence of undescribed resistance mechanisms to triazole- and tetrazole-based sterol 43 demethylase inhibitors.
published_date 2019-06-01T04:01:00Z
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score 11.016235

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