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Systematic and Molecular Basis of the Antibacterial Action of Quinoxaline 1,4-Di-N-Oxides against Escherichia coli.

ABSTRACT: Quinoxaline 1,4-di-N-oxides (QdNOs) are widely known as potent antibacterial agents, but their antibacterial mechanisms are incompletely understood. In this study, the transcriptomic and proteomic profiles of Escherichia coli exposed to QdNOs were integratively investigated, and the results demonstrated that QdNOs mainly induced an SOS response and oxidative stress. Moreover, genes and proteins involved in the bacterial metabolism, cellular structure maintenance, resistance and virulence were also found to be changed, conferring bacterial survival strategies. Biochemical assays showed that reactive oxygen species were induced in the QdNO-treated bacteria and that free radical scavengers attenuated the antibacterial action of QdNOs and DNA damage, suggesting an oxidative-DNA-damage action of QdNOs. The QdNO radical intermediates, likely carbon-centered and aryl-type radicals, as identified by electron paramagnetic resonance, were the major radicals induced by QdNOs, and xanthine oxidase was one of the QdNO-activating enzymes. This study provides new insights into the action of QdNOs in a systematic manner and increases the current knowledge of bacterial physiology under antibiotic stresses, which may be of great value in the development of new antibiotic-potentiating strategies.

SUBMITTER: Cheng G

PROVIDER: S-EPMC4546592 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Systematic and Molecular Basis of the Antibacterial Action of Quinoxaline 1,4-Di-N-Oxides against Escherichia coli.

Cheng Guyue G Li Bei B Wang Chenxi C Zhang Hongfei H Liang Guixia G Weng Zhifei Z Hao Haihong H Wang Xu X Liu Zhenli Z Dai Menghong M Wang Yulian Y Yuan Zonghui Z

PloS one 20150821 8

Quinoxaline 1,4-di-N-oxides (QdNOs) are widely known as potent antibacterial agents, but their antibacterial mechanisms are incompletely understood. In this study, the transcriptomic and proteomic profiles of Escherichia coli exposed to QdNOs were integratively investigated, and the results demonstrated that QdNOs mainly induced an SOS response and oxidative stress. Moreover, genes and proteins involved in the bacterial metabolism, cellular structure maintenance, resistance and virulence were al ...[more]

PMID: 26296207

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Project description:This study aimed to investigate the antibacterial mechanism of cefiderocol (CFDC) using data-independent acquisition quantitative proteomics combined with cellular and molecular biological assays. Numerous differentially expressed proteins related to the production of NADH, reduced cofactor flavin adenine dinucleotide (FADH2), NADPH and reactive oxygen species (ROS), iron-sulfur cluster binding, and iron ion homeostasis were found to be upregulated by CFDC. Furthermore, parallel reaction monitoring analysis validated these results. Meanwhile, we confirmed that the levels of NADH, ROS, H2O2, and iron ions were induced by CFDC, and the sensitivity of Escherichia coli to CFDC was inhibited by the antioxidant vitamin C, N-acetyl-l-cysteine, and deferoxamine. Moreover, deferoxamine also suppressed the H2O2 stress induced by CFDC. In addition, knockout of the NADH-quinone oxidoreductase genes (nuoA, nuoC, nuoE, nuoF, nuoG, nuoJ, nuoL, nuoM) in the respiratory chain attenuated the sensitivity of E. coli to CFDC far beyond the effects of cefepime and ceftazidime; in particular, the E. coli BW25113 ΔnuoJ strain produced 60-fold increases in MIC to CFDC compared to that of the wild-type E. coli BW25113 strain. The present study revealed that CFDC exerts its antibacterial effects by inducing ROS stress by elevating the levels of NADH and iron ions in E. coli. IMPORTANCE CFDC was the first FDA-approved siderophore cephalosporin antibiotic in 2019 and is known for its Trojan horse tactics and broad antimicrobial activity against Gram-negative bacteria. However, its antibacterial mechanism is not fully understood, and whether it has an impact on in vivo iron ion homeostasis remains unknown. To comprehensively reveal the antibacterial mechanisms of CFDC, data-independent acquisition quantitative proteomics combined with cellular and molecular biological assays were performed in this study. The findings will further facilitate our understanding of the antibacterial mechanism of CFDC and may provide a theoretical foundation for controlling CFDC resistance in the future.

Dataset Information

Systematic and Molecular Basis of the Antibacterial Action of Quinoxaline 1,4-Di-N-Oxides against Escherichia coli.

Publications

Systematic and Molecular Basis of the Antibacterial Action of Quinoxaline 1,4-Di-N-Oxides against Escherichia coli.

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