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Literature DB >> 27956419

Fungal CYP51 Inhibitors VT-1161 and VT-1129 Exhibit Strong In Vitro Activity against Candida glabrata and C. krusei Isolates Clinically Resistant to Azole and Echinocandin Antifungal Compounds.

W A Schell¹, A M Jones¹, E P Garvey², W J Hoekstra², R J Schotzinger², B D Alexander³.

Abstract

The in vitro activities of fungal CYP51 inhibitors VT-1161 and VT-1129 were determined for Candida glabrata (n = 34) and C. krusei (n = 50). C. glabrata isolates were screened for FKS gene mutations. All isolates were resistant clinically and/or in vitro to at least one standard antifungal compound. VT-1161 and VT-1129 MICs for all isolates were at least 5-fold below achievable human plasma levels for VT-1161. VT-1161 and VT-1129 are promising for the treatment of resistant C. glabrata and C. krusei infections.

Entities: Chemical Disease Species

Keywords: Candida glabrata; Candida krusei; antifungal susceptibility testing; resistance

Mesh：

Substances：

Year: 2017 PMID： 27956419 PMCID： PMC5328539 DOI： 10.1128/AAC.01817-16

Source DB: PubMed Journal: Antimicrob Agents Chemother ISSN： 0066-4804 Impact factor: 5.191

11 in total

1. Frequency of decreased susceptibility and resistance to echinocandins among fluconazole-resistant bloodstream isolates of Candida glabrata.

Authors: M A Pfaller; M Castanheira; S R Lockhart; A M Ahlquist; S A Messer; R N Jones
Journal: J Clin Microbiol Date: 2012-01-25 Impact factor: 5.948

2. VT-1161 dosed once daily or once weekly exhibits potent efficacy in treatment of dermatophytosis in a guinea pig model.

Authors: E P Garvey; W J Hoekstra; W R Moore; R J Schotzinger; L Long; M A Ghannoum
Journal: Antimicrob Agents Chemother Date: 2015-01-20 Impact factor: 5.191

3. Design and optimization of highly-selective fungal CYP51 inhibitors.

Authors: William J Hoekstra; Edward P Garvey; William R Moore; Stephen W Rafferty; Christopher M Yates; Robert J Schotzinger
Journal: Bioorg Med Chem Lett Date: 2014-06-09 Impact factor: 2.823

4. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database.

Authors: Dimitrios P Kontoyiannis; Kieren A Marr; Benjamin J Park; Barbara D Alexander; Elias J Anaissie; Thomas J Walsh; James Ito; David R Andes; John W Baddley; Janice M Brown; Lisa M Brumble; Alison G Freifeld; Susan Hadley; Loreen A Herwaldt; Carol A Kauffman; Katherine Knapp; G Marshall Lyon; Vicki A Morrison; Genovefa Papanicolaou; Thomas F Patterson; Trish M Perl; Mindy G Schuster; Randall Walker; Kathleen A Wannemuehler; John R Wingard; Tom M Chiller; Peter G Pappas
Journal: Clin Infect Dis Date: 2010-04-15 Impact factor: 9.079

5. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET).

Authors: Peter G Pappas; Barbara D Alexander; David R Andes; Susan Hadley; Carol A Kauffman; Alison Freifeld; Elias J Anaissie; Lisa M Brumble; Loreen Herwaldt; James Ito; Dimitrios P Kontoyiannis; G Marshall Lyon; Kieren A Marr; Vicki A Morrison; Benjamin J Park; Thomas F Patterson; Trish M Perl; Robert A Oster; Mindy G Schuster; Randall Walker; Thomas J Walsh; Kathleen A Wannemuehler; Tom M Chiller
Journal: Clin Infect Dis Date: 2010-04-15 Impact factor: 9.079

6. The Investigational Fungal Cyp51 Inhibitor VT-1129 Demonstrates Potent In Vitro Activity against Cryptococcus neoformans and Cryptococcus gattii.

Authors: Shawn R Lockhart; Annette W Fothergill; Naureen Iqbal; Carol B Bolden; Nina T Grossman; Edward P Garvey; Stephen R Brand; William J Hoekstra; Robert J Schotzinger; Elizabeth Ottinger; Thomas F Patterson; Nathan P Wiederhold
Journal: Antimicrob Agents Chemother Date: 2016-03-25 Impact factor: 5.191

7. Efficacy of the clinical agent VT-1161 against fluconazole-sensitive and -resistant Candida albicans in a murine model of vaginal candidiasis.

Authors: E P Garvey; W J Hoekstra; R J Schotzinger; J D Sobel; E A Lilly; P L Fidel
Journal: Antimicrob Agents Chemother Date: 2015-06-29 Impact factor: 5.191

8. Candida bloodstream infections: comparison of species distributions and antifungal resistance patterns in community-onset and nosocomial isolates in the SENTRY Antimicrobial Surveillance Program, 2008-2009.

Authors: Michael A Pfaller; Gary J Moet; Shawn A Messer; Ronald N Jones; Mariana Castanheira
Journal: Antimicrob Agents Chemother Date: 2010-11-29 Impact factor: 5.191

9. Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint.

Authors: Guillermo Garcia-Effron; Samuel Lee; Steven Park; John D Cleary; David S Perlin
Journal: Antimicrob Agents Chemother Date: 2009-06-22 Impact factor: 5.191

10. Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance.

Authors: Kelley R Healey; Yanan Zhao; Winder B Perez; Shawn R Lockhart; Jack D Sobel; Dimitrios Farmakiotis; Dimitrios P Kontoyiannis; Dominique Sanglard; Saad J Taj-Aldeen; Barbara D Alexander; Cristina Jimenez-Ortigosa; Erika Shor; David S Perlin
Journal: Nat Commun Date: 2016-03-29 Impact factor: 14.919

14 in total

1. Azole Resistance Reduces Susceptibility to the Tetrazole Antifungal VT-1161.

Authors: Brian C Monk; Mikhail V Keniya; Manya Sabherwal; Rajni K Wilson; Danyon O Graham; Harith F Hassan; Danni Chen; Joel D A Tyndall
Journal: Antimicrob Agents Chemother Date: 2018-12-21 Impact factor: 5.191

2. Structural analyses of Candida albicans sterol 14α-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis.

Authors: Tatiana Y Hargrove; Laura Friggeri; Zdzislaw Wawrzak; Aidong Qi; William J Hoekstra; Robert J Schotzinger; John D York; F Peter Guengerich; Galina I Lepesheva
Journal: J Biol Chem Date: 2017-03-03 Impact factor: 5.157

Review 3. CYP51 as drug targets for fungi and protozoan parasites: past, present and future.

Authors: Galina I Lepesheva; Laura Friggeri; Michael R Waterman
Journal: Parasitology Date: 2018-04-12 Impact factor: 3.234

4. VT-1161 protects mice against oropharyngeal candidiasis caused by fluconazole-susceptible and -resistant Candida albicans.

Authors: Timothy J Break; Jigar V Desai; Mukil Natarajan; Elise M N Ferre; Christina Henderson; Adrian M Zelazny; Ulrich Siebenlist; William J Hoekstra; Robert J Schotzinger; Edward P Garvey; Michail S Lionakis
Journal: J Antimicrob Chemother Date: 2018-01-01 Impact factor: 5.790

Review 10. Advances in anti-fungal therapies.

Authors: Grant Waterer
Journal: Mycopathologia Date: 2021-07-15 Impact factor: 2.574