AUTHOR=Ye Jinzhou , Su Yubin , Peng Xuanxian , Li Hui 

TITLE=Reactive Oxygen Species-Related Ceftazidime Resistance Is Caused by the Pyruvate Cycle Perturbation and Reverted by Fe3 + in Edwardsiella tarda

JOURNAL=Frontiers in Microbiology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.654783

DOI=10.3389/fmicb.2021.654783

ISSN=1664-302X

ABSTRACT=<p>Reactive oxygen species (ROS) are related to antibiotic resistance and have been reported in bacteria. However, whether ROS contribute to ceftazidime resistance and plays a role in ceftazidime-mediated killing is unknown. The present study showed lower ROS production in ceftazidime-resistant <italic>Edwardsiella tarda</italic> (LTB4-R<sub><italic>CAZ</italic></sub>) than that in LTB4-sensitive <italic>E. tarda</italic> (LTB4-S), two isogenic <italic>E. tarda</italic> LTB4 strains, which was related to bacterial viability in the presence of ceftazidime. Consistently, ROS promoter Fe<sup>3+</sup> and inhibitor thiourea elevated and reduced the ceftazidime-mediated killing, respectively. Further investigation indicated that the reduction of ROS is related to inactivation of the pyruvate cycle, which provides sources for ROS biosynthesis, but not superoxide dismutase (SOD) and catalase (CAT), which degrade ROS. Interestingly, Fe<sup>3+</sup> promoted the P cycle, increased ROS biosynthesis, and thereby promoted ceftazidime-mediated killing. The Fe<sup>3+</sup>-induced potentiation is generalizable to cephalosporins and clinically isolated multidrug-resistant pathogens. These results show that ROS play a role in bacterial resistance and sensitivity to ceftazidime. More importantly, the present study reveals a previously unknown mechanism that Fe<sup>3+</sup> elevates ROS production via promoting the P cycle.</p>