title: Resistance to ketolide antibiotics by coordinated expression of rRNA methyltransferases in a bacterial producer of natural ketolides.
abstract: Ketolides are promising new antimicrobials effective against a broad range of Gram-positive pathogens, in part because of the low propensity of these drugs to trigger the expression of resistance genes. A natural ketolide pikromycin and a related compound methymycin are produced by Streptomyces venezuelae strain ATCC 15439. The producer avoids the inhibitory effects of its own antibiotics by expressing two paralogous rRNA methylase genes pikR1 and pikR2 with seemingly redundant functions. We show here that the PikR1 and PikR2 enzymes mono- and dimethylate, respectively, the N6 amino group in 23S rRNA nucleotide A2058. PikR1 monomethylase is constitutively expressed; it confers low resistance at low fitness cost and is required for ketolide-induced activation of pikR2 to attain high-level resistance. The regulatory mechanism controlling pikR2 expression has been evolutionary optimized for preferential activation by ketolide antibiotics. The resistance genes and the induction mechanism remain fully functional when transferred to heterologous bacterial hosts. The anticipated wide use of ketolide antibiotics could promote horizontal transfer of these highly efficient resistance genes to pathogens. Taken together, these findings emphasized the need for surveillance of pikR1/pikR2-based bacterial resistance and the preemptive development of drugs that can remain effective against the ketolide-specific resistance mechanism.
authors.affiliation: Center for Pharmaceutical Biotechnology, University of Illinois, Chicago, IL 60607;
authors.forename: Mashal M
authors.initials: MM
authors.lastname: Almutairi
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Sung Ryeol
authors.initials: SR
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense, Denmark;
authors.forename: Simon
authors.initials: S
authors.lastname: Rose
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Hansen
authors.affiliation: Center for Pharmaceutical Biotechnology, University of Illinois, Chicago, IL 60607;
authors.forename: Nora
authors.initials: N
authors.lastname: Vázquez-Laslop
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense, Denmark;
authors.forename: Stephen
authors.initials: S
authors.lastname: Douthwaite
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109; Department of Chemistry, University of Michigan, Ann Arbor, MI 48109.
authors.forename: David H
authors.initials: DH
authors.lastname: Sherman
authors.affiliation: Center for Pharmaceutical Biotechnology, University of Illinois, Chicago, IL 60607; shura@uic.edu.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Mankin
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D048628:Ketolides / Q000494:pharmacology*; D008780:Methyltransferases / Q000235:genetics*; D012338:RNA, Ribosomal, 23S / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D048628:Ketolides; D012338:RNA, Ribosomal, 23S; D008780:Methyltransferases; C035181:rRNA (adenosine-O-2'-)methyltransferase
keywords: antibiotics; ketolides; macrolides; resistance; ribosome