Quinolone tolerance in Escherichia coli dueto defects in the adenosine ribonucleotides de novo biosynthesis pathwayOA
Central carbon metabolism is thought to link reactive oxygen species(ROS)with antibiotic-mediated bacterial death.During enrichment screening of Escherichia coli with the first-generation quinolone oxolinic acid,unstable antibiotic-tolerant mutants containing deficiencies in purB were obtained.Examination of a stable deletion mutant of purA,a gene functionally related to purB,revealed reduced lethality of oxolinic acid and ciprofloxacin.This deletion mutation had little effect on the minimal inhibitory concentration(MIC)of quinolones,thereby demonstrating that the observed protection from killing was attributable to antibiotic tolerance.AMP synthesis was blocked by theΔpurA mutation,and ciprofloxacin tolerance was reversed by exogenous AMP supplementation.Because AMP is a precursor of ATP,interference with ATP synthesis occurs in theΔpurA mutant.RNA-Seq analysis showed that,prior to antibiotic stress,transcript levels of NADH:quinone oxidoreductase genes were reduced by the purA deficiency,thereby predisposing E.coli to antibiotic tolerance through reduced respiration.During ciprofloxacin exposure,the purA deficiency also suppressed the surge in expression of tricarboxylic acid(TCA)cycle and ATP synthesis genes,as well as the accumulation of intracellular ATP and ROS.Thus,wild-type PurA,and by extension the downstream enzyme PurB,directs AMP toward an antibiotic-mediated,ROS-dependent death pathway.Overall,defects in PurA/PurB-mediated adenosine ribonucleotides de novo biosynthesis reveal a novel quinolone tolerance mechanism that is initiated outside central carbon metabolism;tolerance is likely attributable to a limited supply of AMP,resulting in reduced ATP synthesis and suppression of ROS accumulation.
Weiwei Zhu;Yuejuan Nong;Jie Su;Jingwen Yang;Lina Ma;Yunxin Xue;Dai Wang;Jianjun Niu;Karl Drlica;Xilin Zhao
State Key Laboratory of Vaccines for Infectious Diseases,Xiang-An Biomedicine Laboratory,National Innovation Platform for Industry-Education Integration in Vaccine Research,Department of Laboratory Medicine,School of Public Health,Xiamen University,Xiamen,ChinaState Key Laboratory of Vaccines for Infectious Diseases,Xiang-An Biomedicine Laboratory,National Innovation Platform for Industry-Education Integration in Vaccine Research,Department of Laboratory Medicine,School of Public Health,Xiamen University,Xiamen,ChinaState Key Laboratory of Vaccines for Infectious Diseases,Xiang-An Biomedicine Laboratory,National Innovation Platform for Industry-Education Integration in Vaccine Research,Department of Laboratory Medicine,School of Public Health,Xiamen University,Xiamen,ChinaState Key Laboratory of Vaccines for Infectious Diseases,Xiang-An Biomedicine Laboratory,National Innovation Platform for Industry-Education Integration in Vaccine Research,Department of Laboratory Medicine,School of Public Health,Xiamen University,Xiamen,ChinaState Key Laboratory of Vaccines for Infectious Diseases,Xiang-An Biomedicine Laboratory,National Innovation Platform for Industry-Education Integration in Vaccine Research,Department of Laboratory Medicine,School of Public Health,Xiamen University,Xiamen,ChinaState Key Laboratory of Vaccines for Infectious Diseases,Xiang-An Biomedicine Laboratory,National Innovation Platform for Industry-Education Integration in Vaccine Research,Department of Laboratory Medicine,School of Public Health,Xiamen University,Xiamen,ChinaState Key Laboratory of Vaccines for Infectious Diseases,Xiang-An Biomedicine Laboratory,National Innovation Platform for Industry-Education Integration in Vaccine Research,Department of Laboratory Medicine,School of Public Health,Xiamen University,Xiamen,ChinaCenter of Clinical Laboratory,Zhongshan Hospital,School of Medicine,Xiamen University,Xiamen,ChinaPublic Health Research Institute and Department of Microbiology,Biochemistry&Molecular Genetics,New Jersey Medical School,Rutgers University,Newark,New Jersey,USAState Key Laboratory of Vaccines for Infectious Diseases,Xiang-An Biomedicine Laboratory,National Innovation Platform for Industry-Education Integration in Vaccine Research,Department of Laboratory Medicine,School of Public Health,Xiamen University,Xiamen,China
医药卫生
adenosine ribonucleotides de novo biosynthesisAMPantibiotic tolerancePurA/PurBROS
《mLife》 2026 (2)
P.217-228,12
supported in part by the grants from the National Natural Science Foundation of China(82172316 and 8147325)the Scientific Research Foundation of the State Key Laboratory of Vaccines for Infectious Diseases,Xiang-An Biomedicine Laboratory(2023XAKJ0101022)XMU Training Program of Innovation and Entrepreneurship for Undergraduates(S202410384488).
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