DNA damage induced by oxidized pyrimidine nucleotidecontributes to antibiotic lethality
In addition to the well-studied mechanisms of killing through corrupting the function of primary targets, antibiotic-induced metabolic perturbations also have strong impact on antibiotic efficacy. For example, recent studies showed that generation of reactive oxygen species (ROS) as a consequence of metabolic perturbation contributed substantially to cell death by bactericidal antibiotics or other lethal stress. However, the molecular mechanisms through which antibiotic-induced ROS actually kills cells remain largely unresolved.
A research group led by Prof. ZHAO Guoping from CAS Center for Excellence in Molecular Plant Sciences/Shanghai Institute of Plant Physiology and Ecology (SIPPE), Chinese Academy of Science (CAS) and Dr. LYU Liangdong from Fudan University made new progress in the mechanisms ofROS-mediated antibiotic killing.
They found that oxidation of dCTP by antibiotic-induced ROS contributes to antibiotic lethality in stationary-phase mycobacteria. This study provided a model that antibiotic lethality stemming from 5-OH-dCTP relies on ROS production, DnaE2’s incorporation of 5-OH-dCTP into DNA and lethal DNA double-strand breaks (DSBs) generated by incomplete base excision repair via Nth.
This work also demonstrated that the pyrophosphohydrolase MazG encoded by mycobacteria enables house cleaning of 5-OH-dCTP and thus, defense against lethal DNA damage induced by antibiotics. Deletion of mazGin Mycobacterium tuberculosis, the causative agent of tuberculosis, results in increased antibiotic killing upon stationary-phase culture.
This work exemplifies how the events downstream of antibiotic-target interaction could influence antibiotic efficacy. Since lethality stemming from 5-OH-dCTP is only relevant in stationary phase, a multi-stress and non-growing physiological state that is known to be associated with drug tolerance and mutagenesis, this finding may have broad implications not only to antibiotic lethality but also to the mechanism of stress-induced mutagenesis in bacteria.
The work was supported by Chinese National Mega Science and Technology Program and National Natural Science Foundation.
1. Prof. Guoping ZHAO
CAS Center for Excellence in Molecular Plant Sciences/Shanghai Institute of Plant Physiology and Ecology (SIPPE)
2. LYU Liangdong
Maintenance of genome integrity plays a critical role for antibiotic tolerance