title: Ribosomal mutations promote the evolution of antibiotic resistance in a multidrug environment.
abstract: Antibiotic resistance arising via chromosomal mutations is typically specific to a particular antibiotic or class of antibiotics. We have identified mutations in genes encoding ribosomal components inMycobacterium smegmatisthat confer resistance to several structurally and mechanistically unrelated classes of antibiotics and enhance survival following heat shock and membrane stress. These mutations affect ribosome assembly and cause large-scale transcriptomic and proteomic changes, including the downregulation of the catalase KatG, an activating enzyme required for isoniazid sensitivity, and upregulation of WhiB7, a transcription factor involved in innate antibiotic resistance. Importantly, while these ribosomal mutations have a fitness cost in antibiotic-free medium, in a multidrug environment they promote the evolution of high-level, target-based resistance. Further, suppressor mutations can then be easily acquired to restore wild-type growth. Thus, ribosomal mutations can serve as stepping-stones in an evolutionary path leading to the emergence of high-level, multidrug resistance.
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, United States.
authors.forename: James E
authors.identifier: 0000-0002-2640-7453
authors.initials: JE
authors.lastname: Gomez
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, United States.|Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, United States.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States.
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Kaufmann-Malaga
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, United States.|Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, United States.
authors.forename: Carl N
authors.initials: CN
authors.lastname: Wivagg
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, United States.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Kim
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, United States.
authors.forename: Melanie R
authors.identifier: 0000-0002-0732-9744
authors.initials: MR
authors.lastname: Silvis
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, United States.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Renedo
authors.affiliation: Department of Computer Science, Texas A&M University, College Station, United States.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Ioerger
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, United States.
authors.forename: Rushdy
authors.initials: R
authors.lastname: Ahmad
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Livny
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, United States.
authors.forename: Skye
authors.initials: S
authors.lastname: Fishbein
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, United States.
authors.forename: James C
authors.initials: JC
authors.lastname: Sacchettini
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, United States.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Carr
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, United States.|Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, United States.|Department of Genetics, Harvard Medical School, Boston, United States.
authors.forename: Deborah T
authors.identifier: 0000-0003-4262-0673
authors.initials: DT
authors.lastname: Hung
mesh_terms: D001426:Bacterial Proteins / Q000096:biosynthesis; D024881:Drug Resistance, Bacterial; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial; D009154:Mutation; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000235:genetics*; D020543:Proteome / Q000032:analysis; D012270:Ribosomes / Q000187:drug effects* / Q000235:genetics*
chemical_list: D001426:Bacterial Proteins; D020543:Proteome
keywords: Mycobacterium; antibiotic resistance; evolutionary biology; fluoroquinolones; genomics; infectious disease; microbiology; ribosome