Oxidation of dCTP Contributes to Antibiotic Lethality in Stationary-phase Mycobacteria
Publication in refereed journal



摘要Growing evidence shows that generation of reactive oxygen species (ROS) derived from antibiotic-induced metabolic perturbation contribute to antibiotic lethality. However, our knowledge of the mechanisms by which antibiotic-induced oxidative stress actually kills cells remains elusive. Here, we show that oxidation of dCTP underlies ROS-mediated antibiotic lethality via induction of DNA double-strand breaks (DSBs). Deletion of mazG-encoded 5-OH-dCTP–specific pyrophosphohydrolase potentiates antibiotic killing of stationary-phase mycobacteria, but did not affect antibiotic efficacy in exponentially growing cultures. Critically, the effect of mazG deletion on potentiating antibiotic killing is associated with antibiotic-induced ROS and accumulation of 5-OH-dCTP. Independent lines of evidence presented here indicate that the increased level of DSBs observed in the ΔmazG mutant is a dead-end event accounting for enhanced antibiotic killing. Moreover, we provided genetic evidence that 5-OH-dCTP is incorporated into genomic DNA via error-prone DNA polymerase DnaE2 and repair of 5-OH-dC lesions via the endonuclease Nth leads to the generation of lethal DSBs. This work provides a mechanistic view of ROS-mediated antibiotic lethality in stationary phase and may have broad implications not only with respect to antibiotic lethality but also to the mechanism of stress-induced mutagenesis in bacteria.
著者Xiao-Yong Fan, Bi-Kui Tang, Yuan-Yuan Xu, Ang-Xuan Han, Kun-Xiong Shi, Yong-Kai Wu, Yu Ye, Mei-li Wei, Chen Niu, Ka-Wing Wong, Guo-Ping Zhao, Liang-Dong Lyu
期刊名稱Proceedings of the National Academy of Sciences
頁次2210 - 2215
關鍵詞DNA double-strand breaks, 5-OH-dCTP, reactive oxygen species, antibiotic, Mycobacterium

上次更新時間 2020-23-11 於 01:43