Clinically relevant mutations in core metabolic genes confer antibiotic resistance

Allison J. Lopatkin; Sarah C. Bening; Abigail L. Manson; Jonathan M. Stokes; Michael A. Kohanski; Ahmed H. Badran; Ashlee M. Earl; Nicole J. Cheney; Jason H. Yang; James J. Collins

doi:10.1126/science.aba0862

Research Article

Clinically relevant mutations in core metabolic genes confer antibiotic resistance

View ORCID ProfileAllison J. Lopatkin¹,²,³,⁴,⁵,⁶,
View ORCID ProfileSarah C. Bening¹,²,
View ORCID ProfileAbigail L. Manson²,
Jonathan M. Stokes¹,²,³,
View ORCID ProfileMichael A. Kohanski⁷,
View ORCID ProfileAhmed H. Badran ²,
View ORCID ProfileAshlee M. Earl ²,
View ORCID ProfileNicole J. Cheney⁸,⁹,
View ORCID ProfileJason H. Yang ⁸,⁹,
View ORCID ProfileJames J. Collins ¹,²,³,¹⁰,¹¹,*

¹Institute for Medical Engineering and Science and Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA.
²Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³Wyss Institute for Biologically Inspired Engineering; Harvard University, Boston, MA, USA.
⁴Department of Biology, Barnard College, New York, NY, USA.
⁵Data Science Institute, Columbia University, New York, NY, USA.
⁶Ecology, Evolution, and Environmental Biology, Columbia University, New York, NY, USA.
⁷Department of Otorhinolaryngology-Head and Neck Surgery, Division of Rhinology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁸Ruy V. Lourenço Center for Emerging and Re-Emerging Pathogens, Rutgers New Jersey Medical School, Newark, NJ, USA.
⁹Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, USA.
¹⁰Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹¹Harvard-MIT Program in Health Sciences and Technology, Cambridge, MA, USA.

↵*Corresponding author. Email: jimjc{at}mit.edu

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Science 19 Feb 2021:
Vol. 371, Issue 6531, eaba0862
DOI: 10.1126/science.aba0862

Allison J. Lopatkin

1Institute for Medical Engineering and Science and Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA.

2Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

3Wyss Institute for Biologically Inspired Engineering; Harvard University, Boston, MA, USA.

4Department of Biology, Barnard College, New York, NY, USA.

5Data Science Institute, Columbia University, New York, NY, USA.

6Ecology, Evolution, and Environmental Biology, Columbia University, New York, NY, USA.

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ORCID record for Allison J. Lopatkin

Sarah C. Bening

1Institute for Medical Engineering and Science and Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA.

2Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

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Abigail L. Manson

2Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

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Jonathan M. Stokes

1Institute for Medical Engineering and Science and Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA.

2Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

3Wyss Institute for Biologically Inspired Engineering; Harvard University, Boston, MA, USA.

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Michael A. Kohanski

7Department of Otorhinolaryngology-Head and Neck Surgery, Division of Rhinology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

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Ahmed H. Badran

2Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

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Ashlee M. Earl

2Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

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Nicole J. Cheney

8Ruy V. Lourenço Center for Emerging and Re-Emerging Pathogens, Rutgers New Jersey Medical School, Newark, NJ, USA.

9Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, USA.

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Jason H. Yang

8Ruy V. Lourenço Center for Emerging and Re-Emerging Pathogens, Rutgers New Jersey Medical School, Newark, NJ, USA.

9Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, USA.

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James J. Collins

1Institute for Medical Engineering and Science and Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA.

2Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

3Wyss Institute for Biologically Inspired Engineering; Harvard University, Boston, MA, USA.

10Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA, USA.

11Harvard-MIT Program in Health Sciences and Technology, Cambridge, MA, USA.

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For correspondence: jimjc@mit.edu

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The many roads to resistance

Antibiotic resistance arising from mutation is common among pathogenic bacteria. However, this process is not well understood, and most of the mutations that have been identified to confer resistance do so by modification of the intracellular target or enzymes that can disable the antibacterial compound within the cell. Screening for the evolution of resistance at different temperatures, Lopatkin et al. found that mutations that affect microbial metabolism can result in antibiotic resistance (see the Perspective by Zampieri). These mutations targeted central carbon and energy metabolism and revealed novel resistance mutations in core metabolic genes, expanding the known means by which pathogenic microbes can evolve resistance.

Science, this issue p. eaba0862; see also p. 783

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Clinically relevant mutations in core metabolic genes confer antibiotic resistance

The many roads to resistance

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