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Sub-inhibitory fosmidomycin exposures elicits oxidative stress in Salmonella enterica Serovar typhimurium LT2

Fox, David T. and Schmidt, Emily N. and Tian, Hongzhao and Dhungana, Suraj and Valentine, Michael C. and Warrington, Nicole V. and Phillips, Paul D. and Finney, Kellan B. and Cope, Emily K. and Leid, Jeff G. and Testa, Charles A. and Koppisch, Andrew T. (2014) Sub-inhibitory fosmidomycin exposures elicits oxidative stress in Salmonella enterica Serovar typhimurium LT2. Plos One, 9 (4). e95271. ISSN 1932-6203

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Publisher’s or external URL: http://dx.doi.org/10.1371/journal.pone.0095271


Fosmidomycin is a time-dependent nanomolar inhibitor of methylerythritol phosphate (MEP) synthase, which is the enzyme that catalyzes the first committed step in the MEP pathway to isoprenoids. Importantly, fosmidomycin is one of only a few MEP pathway-specific inhibitors that exhibits antimicrobial activity. Most inhibitors identified to date only exhibit activity against isolated pathway enzymes. The MEP pathway is the sole route to isoprenoids in many bacteria, yet has no human homologs. The development of inhibitors of this pathway holds promise as novel antimicrobial agents. Similarly, analyses of the bacterial response toward MEP pathway inhibitors provides valuable information toward the understanding of how emergent resistance may ultimately develop to this class of antibiotics. We have examined the transcriptional response of Salmonella enterica serovar typhimurium LT2 to sub-inhibitory concentrations of fosmidomycin via cDNA microarray and RTPCR. Within the regulated genes identified by microarray were a number of genes encoding enzymes associated with the mediation of reactive oxygen species (ROS). Regulation of a panel of genes implicated in the response of cells to oxidative stress (including genes for catalases, superoxide dismutases, and alkylhydrogen peroxide reductases) was investigated and mild upregulation in some members was observed as a function of fosmidomycin exposure over time. The extent of regulation of these genes was similar to that observed for comparable exposures to kanamycin, but differed significantly from tetracycline. Furthermore, S. typhimurium exposed to sub-inhibitory concentrations of fosmidomycin displayed an increased sensitivity to exogenous H2O2 relative to either untreated controls or kanamycin-treated cells. Our results suggest that endogenous oxidative stress is one consequence of exposures to fosmidomycin, likely through the temporal depletion of intracellular isoprenoids themselves, rather than other mechanisms that have been proposed to facilitate ROS accumulation in bacteria (e.g. cell death processes or the ability of the antibiotic to redox cycle).

Item Type: Article
ID number or DOI: 10.1371/journal.pone.0095271
Subjects: Q Science > QH Natural history > QH426 Genetics
Q Science > QR Microbiology
NAU Depositing Author Academic Status: Faculty/Staff
Department/Unit: College of Engineering, Forestry, and Natural Science > Chemistry and Biochemistry
Date Deposited: 09 Nov 2015 20:12
URI: http://openknowledge.nau.edu/id/eprint/1727

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