| Autor: |
Gomez JE; The Broad Institute of MIT and Harvard, Cambridge, United States., Kaufmann-Malaga BB; 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., Wivagg CN; 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., Kim PB; The Broad Institute of MIT and Harvard, Cambridge, United States., Silvis MR; The Broad Institute of MIT and Harvard, Cambridge, United States., Renedo N; The Broad Institute of MIT and Harvard, Cambridge, United States., Ioerger TR; Department of Computer Science, Texas A&M University, College Station, United States., Ahmad R; The Broad Institute of MIT and Harvard, Cambridge, United States., Livny J; The Broad Institute of MIT and Harvard, Cambridge, United States., Fishbein S; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, United States., Sacchettini JC; Department of Biochemistry and Biophysics, Texas A&M University, College Station, United States., Carr SA; The Broad Institute of MIT and Harvard, Cambridge, United States., Hung DT; 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. |
| Abstrakt: |
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 in Mycobacterium smegmatis that 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. |
