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Guanosine tetra- and pentaphosphate increase antibiotic tolerance by reducing reactive oxygen species production in Vibrio cholerae

 Hwa Young Kim  ;  Junhyeok Go  ;  Kang-Mu Lee  ;  Young Taek Oh  ;  Sang Sun Yoon 
 Journal of Biological Chemistry, Vol.293(15) : 5679-5694, 2018 
Journal Title
 Journal of Biological Chemistry 
Issue Date
ROS ; Vibrio cholerae ; alarmone ; antibiotic resistance ; antibiotic tolerance ; bacterial metabolism ; bacterial pathogenesis ; cholera ; guanosine tetra- and pentaphosphate ; iron uptake ; oxidative stress ; stress response ; stress signaling ; stringent response
The pathogen Vibrio cholerae is the causative agent of cholera. Emergence of antibiotic-resistant V. cholerae strains is increasing, but the underlying mechanisms remain unclear. Herein, we report that the stringent response regulator and stress alarmone guanosine tetra- and pentaphosphate ((p)ppGpp) significantly contributes to antibiotic tolerance in V. cholerae We found that N16961, a pandemic V. cholerae strain, and its isogenic (p)ppGpp-overexpressing mutant DeltarelADeltaspoT are both more antibiotic-resistant than (p)ppGpp(0) (DeltarelADeltarelVDeltaspoT) and DeltadksA mutants, which cannot produce or utilize (p)ppGpp, respectively. We also found that additional disruption of the aconitase B-encoding and tricarboxylic acid (TCA) cycle gene acnB in the (p)ppGpp(0) mutant increases its antibiotic tolerance. Moreover, expression of TCA cycle genes, including acnB, was increased in (p)ppGpp(0), but not in the antibiotic-resistant DeltarelADeltaspoT mutant, suggesting that (p)ppGpp suppresses TCA cycle activity, thereby entailing antibiotic resistance. Importantly, when grown anaerobically or incubated with an iron chelator, the (p)ppGpp(0) mutant became antibiotic-tolerant, suggesting that reactive oxygen species (ROS) are involved in antibiotic-mediated bacterial killing. Consistent with that hypothesis, tetracycline treatment markedly increased ROS production in the antibiotic-susceptible mutants. Interestingly, expression of the Fe(III) ABC transporter substrate-binding protein FbpA was increased 10-fold in (p)ppGpp(0), and fbpA gene deletion restored viability of tetracycline-exposed (p)ppGpp(0) cells. Of note, FbpA expression was repressed in the (p)ppGpp-accumulating mutant, resulting in a reduction of intracellular free iron, required for the ROS-generating Fenton reaction. Our results indicate that (p)ppGpp-mediated suppression of central metabolism and iron uptake reduces antibiotic-induced oxidative stress in V. cholerae.
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1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실)
Yonsei Authors
윤상선(Yoon, Sang Sun)
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