Spontaneous Selection of Cryptosporidium Drug Resistance in a Calf Model of Infection.
| Autor: | Hasan MM; Cellular, Molecular and Biomedical Sciences Graduate Program, University of Vermont, Burlington, Vermont, USA., Stebbins EE; Department of Medicine, University of Vermont Larner College of Medicine, Burlington, Vermont, USA., Choy RKM; PATH, San Francisco, California, USA., Gillespie JR; Department of Medicine, University of Washington, Seattle, Washington, USA., de Hostos EL; PATH, San Francisco, California, USA., Miller P; Department of Medicine, University of Vermont Larner College of Medicine, Burlington, Vermont, USA., Mushtaq A; Department of Medicine, University of Washington, Seattle, Washington, USA., Ranade RM; Department of Medicine, University of Washington, Seattle, Washington, USA., Teixeira JE; Department of Medicine, University of Vermont Larner College of Medicine, Burlington, Vermont, USA., Verlinde CLMJ; Department of Biochemistry, University of Washington, Seattle, Washington, USA., Sateriale A; The Francis Crick Institute, London, United Kingdom., Zhang Z; Department of Biochemistry, University of Washington, Seattle, Washington, USA., Osbourn DM; Department of Molecular Microbiology and Immunology, Saint Louis University, St. Louis, Missouri, USA., Griggs DW; Department of Molecular Microbiology and Immunology, Saint Louis University, St. Louis, Missouri, USA., Fan E; Department of Biochemistry, University of Washington, Seattle, Washington, USA., Buckner FS; Department of Medicine, University of Washington, Seattle, Washington, USA FBuckner@medicine.washington.edu christopher.huston@uvm.edu., Huston CD; Cellular, Molecular and Biomedical Sciences Graduate Program, University of Vermont, Burlington, Vermont, USA FBuckner@medicine.washington.edu christopher.huston@uvm.edu.; Department of Medicine, University of Vermont Larner College of Medicine, Burlington, Vermont, USA. |
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| Jazyk: | angličtina |
| Zdroj: | Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2021 May 18; Vol. 65 (6). Date of Electronic Publication: 2021 May 18 (Print Publication: 2021). |
| DOI: | 10.1128/AAC.00023-21 |
| Abstrakt: | The intestinal protozoan Cryptosporidium is a leading cause of diarrheal disease and mortality in young children. There is currently no fully effective treatment for cryptosporidiosis, which has stimulated interest in anticryptosporidial development over the last ∼10 years, with numerous lead compounds identified, including several tRNA synthetase inhibitors. Here, we report the results of a dairy calf efficacy trial of the methionyl-tRNA ( Cryptosporidium parvum MetRS [ Cp MetRS]) synthetase inhibitor 2093 and the spontaneous emergence of drug resistance. Dairy calves experimentally infected with Cryptosporidium parvum initially improved with 2093 treatment, but parasite shedding resumed in two of three calves on treatment day 5. Parasites shed by each recrudescent calf had different amino acid-altering mutations in the gene encoding Cp MetRS ( CpMetRS ), yielding either an aspartate 243-to-glutamate (D243E) or a threonine 246-to-isoleucine (T246I) mutation. Transgenic parasites engineered to have either the D243E or T246I Cp MetRS mutation using CRISPR/Cas9 grew normally but were highly 2093 resistant; the D243E and T246I mutant-expressing parasites, respectively, had 2093 half-maximal effective concentrations (EC (Copyright © 2021 American Society for Microbiology.) |
| Databáze: | MEDLINE |
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