Lethality of MalE-LacZ hybrid protein shares mechanistic attributes with oxidative component of antibiotic lethality
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Author(s)
Liu, Xiaobo
Andreescu, Silvana
Takahashi, Noriko
Gruber, Charley C
Yang, Jason Hung-Ying
Braff, Dana
Yashaswini, Chittampalli N.
Bhubhanil, Sakkarin
Furuta, Yoshikazu
Collins, James J.
Date Issued
August 2017
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Takahashi, Noriko et al. “Lethality of MalE-LacZ Hybrid Protein Shares Mechanistic Attributes with Oxidative Component of Antibiotic Lethality.” Proceedings of the National Academy of Sciences 114, 34 (August 2017): 9164–9169 © 2017 National Academy of Sciences
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Final published version
Abstract
Downstream metabolic events can contribute to the lethality of drugs or agents that interact with a primary cellular target. In bacteria, the production of reactive oxygen species (ROS) has been associated with the lethal effects of a variety of stresses including bactericidal antibiotics, but the relative contribution of this oxidative component to cell death depends on a variety of factors. Experimental evidence has suggested that unresolvable DNA problems caused by incorporation of oxidized nucleotides into nascent DNA followed by incomplete base excision repair contribute to the ROS-dependent component of antibiotic lethality. Expression of the chimeric periplasmic-cytoplasmic MalE-LacZ[subscript 72 – 47] protein is an historically important lethal stress originally identified during seminal genetic experiments that defined the SecY-dependent protein translocation system. Multiple, independent lines of evidence presented here indicate that the predominant mechanism for MalE-LacZ lethality shares attributes with the ROS-dependent component of antibiotic lethality. MalE-LacZ lethality requires molecular oxygen, and its expression induces ROS production. The increased susceptibility of mutants sensitive to oxidative stress to MalE-LacZ lethality indicates that ROS contribute causally to cell death rather than simply being produced by dying cells. Observations that support the proposed mechanism of cell death include MalE-LacZ expression being bacteriostatic rather than bactericidal in cells that over-express MutT, a nucleotide sanitizer that hydrolyzes 8-oxo-dGTP to the monophosphate, or that lack MutM and MutY, DNA glycosylases that process base pairs involving 8-oxo-dGTP. Our studies suggest stress-induced physiological changes that favor this mode of ROS-dependent death.
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
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DOI of Published Version
https://doi.org/10.1073/PNAS.1707466114
