BACKGROUND: Candida albicans, the most common human fungal pathogen, causes chronic mucosal infections in patients with inborn errors of IL-17 immunity that rely heavily on chronic, often lifelong, azole antifungal agents for treatment. However, a rise in azole resistance has predicated a need for developing new antifungal drugs. OBJECTIVES: To test the in vitro and in vivo efficacy of VT-1161 and VT-1129 in the treatment of oropharyngeal candidiasis with azole-susceptible or -resistant C. albicans strains. METHODS: MICs of VT-1161, VT-1129 and nine licensed antifungal drugs were determined for 31 Candida clinical isolates. The drug concentrations in mouse serum and tongues were measured following oral administration. IL-17-signalling-deficient Act1-/- mice were infected with fluconazole-susceptible or fluconazole-resistant C. albicans strains, and the amount of mucosal fungal burden was determined after fluconazole or VT-1161 treatment. RESULTS: Fourteen isolates (45%) were not fluconazole susceptible (MIC ≥4 mg/L). VT-1161 and VT-1129 showed significant in vitro activity against the majority of the 31 mucosal clinical isolates (MIC50 0.03 and 0.06 mg/L, respectively), including Candida glabrata (MIC50, 0.125 and 0.25 mg/L, respectively). After oral doses, VT-1161 and VT-1129 concentrations in mouse serum and tongues were well above their MIC50 values. VT-1161 was highly effective as treatment of both fluconazole-susceptible and -resistant oropharyngeal candidiasis in Act1-/- mice. CONCLUSIONS: VT-1129 and VT-1161 exhibit significant in vitro activity against Candida strains, including fluconazole-resistant C. albicans and C. glabrata. VT-1161 administration in mice results in significant mucosal drug accumulation and eradicates infection caused by fluconazole-susceptible and -resistant Candida strains. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy 2017. This work is written by US Government employees and is in the public domain in the US.
BACKGROUND: Candida albicans, the most common human fungal pathogen, causes chronic mucosal infections in patients with inborn errors of IL-17 immunity that rely heavily on chronic, often lifelong, azole antifungal agents for treatment. However, a rise in azole resistance has predicated a need for developing new antifungal drugs. OBJECTIVES: To test the in vitro and in vivo efficacy of VT-1161 and VT-1129 in the treatment of oropharyngeal candidiasis with azole-susceptible or -resistant C. albicans strains. METHODS: MICs of VT-1161, VT-1129 and nine licensed antifungal drugs were determined for 31 Candida clinical isolates. The drug concentrations in mouse serum and tongues were measured following oral administration. IL-17-signalling-deficient Act1-/- mice were infected with fluconazole-susceptible or fluconazole-resistant C. albicans strains, and the amount of mucosal fungal burden was determined after fluconazole or VT-1161 treatment. RESULTS: Fourteen isolates (45%) were not fluconazole susceptible (MIC ≥4 mg/L). VT-1161 and VT-1129 showed significant in vitro activity against the majority of the 31 mucosal clinical isolates (MIC50 0.03 and 0.06 mg/L, respectively), including Candida glabrata (MIC50, 0.125 and 0.25 mg/L, respectively). After oral doses, VT-1161 and VT-1129 concentrations in mouse serum and tongues were well above their MIC50 values. VT-1161 was highly effective as treatment of both fluconazole-susceptible and -resistant oropharyngeal candidiasis in Act1-/- mice. CONCLUSIONS: VT-1129 and VT-1161 exhibit significant in vitro activity against Candida strains, including fluconazole-resistant C. albicans and C. glabrata. VT-1161 administration in mice results in significant mucosal drug accumulation and eradicates infection caused by fluconazole-susceptible and -resistant Candida strains. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy 2017. This work is written by US Government employees and is in the public domain in the US.
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
Authors: Elise M N Ferre; Stacey R Rose; Sergio D Rosenzweig; Peter D Burbelo; Kimberly R Romito; Julie E Niemela; Lindsey B Rosen; Timothy J Break; Wenjuan Gu; Sally Hunsberger; Sarah K Browne; Amy P Hsu; Shakuntala Rampertaap; Muthulekha Swamydas; Amanda L Collar; Heidi H Kong; Chyi-Chia Richard Lee; David Chascsa; Thomas Simcox; Angela Pham; Anamaria Bondici; Mukil Natarajan; Joseph Monsale; David E Kleiner; Martha Quezado; Ilias Alevizos; Niki M Moutsopoulos; Lynne Yockey; Cathleen Frein; Ariane Soldatos; Katherine R Calvo; Jennifer Adjemian; Morgan N Similuk; David M Lang; Kelly D Stone; Gulbu Uzel; Jeffrey B Kopp; Rachel J Bishop; Steven M Holland; Kenneth N Olivier; Thomas A Fleisher; Theo Heller; Karen K Winer; Michail S Lionakis Journal: JCI Insight Date: 2016-08-18
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
Authors: Lisa F Shubitz; Michael E Roy; Hien T Trinh; William J Hoekstra; Robert J Schotzinger; Edward P Garvey Journal: Antimicrob Agents Chemother Date: 2017-04-24 Impact factor: 5.191
Authors: Teclegiorgis Gebremariam; Nathan P Wiederhold; Annette W Fothergill; Edward P Garvey; William J Hoekstra; Robert J Schotzinger; Thomas F Patterson; Scott G Filler; Ashraf S Ibrahim Journal: Antimicrob Agents Chemother Date: 2015-09-14 Impact factor: 5.191
Authors: Lisa F Shubitz; Hien T Trinh; John N Galgiani; Maria L Lewis; Annette W Fothergill; Nathan P Wiederhold; Bridget M Barker; Eric R G Lewis; Adina L Doyle; William J Hoekstra; Robert J Schotzinger; Edward P Garvey Journal: Antimicrob Agents Chemother Date: 2015-09-14 Impact factor: 5.191
Authors: Heather R Conti; Alanna C Peterson; Lucas Brane; Anna R Huppler; Nydiaris Hernández-Santos; Natasha Whibley; Abhishek V Garg; Michelle R Simpson-Abelson; Gregory A Gibson; Anna J Mamo; Lisa C Osborne; Shrinivas Bishu; Nico Ghilardi; Ulrich Siebenlist; Simon C Watkins; David Artis; Mandy J McGeachy; Sarah L Gaffen Journal: J Exp Med Date: 2014-09-08 Impact factor: 14.307
Authors: Timothy J Break; Jigar V Desai; Kelley R Healey; Mukil Natarajan; Elise M N Ferre; Christina Henderson; Adrian Zelazny; Ulrich Siebenlist; Christopher M Yates; Oren J Cohen; Robert J Schotzinger; David S Perlin; Edward P Garvey; Michail S Lionakis Journal: J Antimicrob Chemother Date: 2018-08-01 Impact factor: 5.790
Authors: Jigar V Desai; Amanda Urban; Michail S Lionakis; Alexandra F Freeman; Doris Z Swaim; Benjamin Colton; Lilian W Kibathi; Elise M N Ferrè; Pamela Stratton; Melissa A Merideth; Sally Hunsberger; Theresa Matkovits; Raphael Mannino; Steven M Holland; Edmund Tramont Journal: Antimicrob Agents Chemother Date: 2022-06-14 Impact factor: 5.938
Authors: Timothy J Break; Vasileios Oikonomou; Nicolas Dutzan; Jigar V Desai; Marc Swidergall; Tilo Freiwald; Daniel Chauss; Oliver J Harrison; Julie Alejo; Drake W Williams; Stefania Pittaluga; Chyi-Chia R Lee; Nicolas Bouladoux; Muthulekha Swamydas; Kevin W Hoffman; Teresa Greenwell-Wild; Vincent M Bruno; Lindsey B Rosen; Wint Lwin; Andy Renteria; Sergio M Pontejo; John P Shannon; Ian A Myles; Peter Olbrich; Elise M N Ferré; Monica Schmitt; Daniel Martin; Daniel L Barber; Norma V Solis; Luigi D Notarangelo; David V Serreze; Mitsuru Matsumoto; Heather D Hickman; Philip M Murphy; Mark S Anderson; Jean K Lim; Steven M Holland; Scott G Filler; Behdad Afzali; Yasmine Belkaid; Niki M Moutsopoulos; Michail S Lionakis Journal: Science Date: 2021-01-15 Impact factor: 47.728
Authors: Patrick Van Dijck; Jelmer Sjollema; Bruno P Cammue; Katrien Lagrou; Judith Berman; Christophe d'Enfert; David R Andes; Maiken C Arendrup; Axel A Brakhage; Richard Calderone; Emilia Cantón; Tom Coenye; Paul Cos; Leah E Cowen; Mira Edgerton; Ana Espinel-Ingroff; Scott G Filler; Mahmoud Ghannoum; Neil A R Gow; Hubertus Haas; Mary Ann Jabra-Rizk; Elizabeth M Johnson; Shawn R Lockhart; Jose L Lopez-Ribot; Johan Maertens; Carol A Munro; Jeniel E Nett; Clarissa J Nobile; Michael A Pfaller; Gordon Ramage; Dominique Sanglard; Maurizio Sanguinetti; Isabel Spriet; Paul E Verweij; Adilia Warris; Joost Wauters; Michael R Yeaman; Sebastian A J Zaat; Karin Thevissen Journal: Microb Cell Date: 2018-06-14