title: Mutation of the mitochondrial large ribosomal RNA can provide pentamidine resistance to Saccharomyces cerevisiae.
abstract: Pentamidine is used to treat several trypanosomal diseases, as well as opportunistic infection by pathogenic fungi. However, the relevant targets of this drug are unknown. We isolated dominant mutations providing pentamidine resistance to Saccharomyces cerevisiae, one of which was localized to mitochondrial DNA. Next-generation sequencing revealed alteration of a widely conserved base at the peptidyl transferase center of the mitochondrial 21S ribosomal RNA. Our results provide a potential rationale for the toxicity of this drug to patients, and we discuss whether blockade of mitochondrial translation is the mechanism by which pathogenic fungi or protists are killed by pentamidine.
authors.affiliation: Department of Molecular Biology and Genetics, Koç University, Sarıyer, İstanbul 34450, Turkey.
authors.forename: Ş Tomris
authors.initials: ŞT
authors.lastname: Örs
authors.affiliation: Department of Molecular Biology and Genetics, Koç University, Sarıyer, İstanbul 34450, Turkey.
authors.forename: Emel
authors.initials: E
authors.lastname: Akdoğan
authors.affiliation: Department of Molecular Biology and Genetics, Koç University, Sarıyer, İstanbul 34450, Turkey. Electronic address: cdunn@ku.edu.tr.
authors.forename: Cory D
authors.initials: CD
authors.lastname: Dunn
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D025141:Drug Resistance, Fungal; D059014:High-Throughput Nucleotide Sequencing; D008969:Molecular Sequence Data; D009154:Mutation; D010419:Pentamidine / Q000494:pharmacology*; D012313:RNA / Q000235:genetics*; D000077278:RNA, Mitochondrial; D012335:RNA, Ribosomal / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: C454219:21S rRNA; D000935:Antifungal Agents; D000077278:RNA, Mitochondrial; D012335:RNA, Ribosomal; D012313:RNA; D010419:Pentamidine
keywords: Anti-microbial; Antibiotic; Mitochondrial translation; Pneumocystis; Trypanosome