Lethality of MalE-LacZ hybrid protein shares mechanistic attributes with oxidative component of antibiotic lethality
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.; Walker, Graham C.; ... Show more Show less![Thumbnail](/bitstream/handle/1721.1/114885/9164.full.pdf.jpg?sequence=6&isAllowed=y)
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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.
Date issued
2017-08Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science; Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of BiologyJournal
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
Version: Final published version
ISSN
0027-8424
1091-6490