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

Guyue Cheng; Bei Li; Chenxi Wang; Hongfei Zhang; Guixia Liang; Zhifei Weng; Haihong Hao; Xu Wang; Zhenli Liu; Menghong Dai; Yulian Wang; Zonghui Yuan

doi:10.1371/journal.pone.0136450

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

PLoS One. 2015 Aug 21;10(8):e0136450. doi: 10.1371/journal.pone.0136450. eCollection 2015.

Authors

Guyue Cheng¹, Bei Li², Chenxi Wang², Hongfei Zhang², Guixia Liang², Zhifei Weng², Haihong Hao¹, Xu Wang¹, Zhenli Liu³, Menghong Dai¹, Yulian Wang³, Zonghui Yuan⁴

Affiliations

¹ MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, 430070, China; Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
² MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
³ National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei, 430070, China; Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
⁴ MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, 430070, China; National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei, 430070, China; Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / pharmacology*
Cell Survival / drug effects
DNA Damage
Dose-Response Relationship, Drug
Escherichia coli / drug effects*
Escherichia coli / genetics
Escherichia coli / growth & development
Escherichia coli / metabolism
Gene Expression Regulation, Bacterial
Microbial Sensitivity Tests
Molecular Sequence Annotation
Oxidation-Reduction
Oxidative Stress
Protein Biosynthesis / drug effects
Proteomics
Quinoxalines / pharmacology*
Reactive Oxygen Species / agonists
Reactive Oxygen Species / metabolism
SOS Response, Genetics / drug effects
Structure-Activity Relationship
Tirapazamine
Triazines / pharmacology*

Substances

Anti-Bacterial Agents
Mequindox
Quinoxalines
Reactive Oxygen Species
Triazines
Tirapazamine
cyadox
olaquindox

Grants and funding

The research was supported by the National High Technology Research and Development Program of China (2011AA10A214) (www.most.gov.cn) to MD, the National Program for Risk Assessment of Quality and Safety of Livestock and Poultry Products (GJFP2015008) (www.moa.gov.cn) to ZY, the National Natural Science Foundation of China (31272614) (www.nsfc.gov.cn) to XW and the Fundamental Research Funds for the Central Universities of China (2013QC002) (www.moe.gov.cn) to GC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.