Abstract
Quinoxaline 1,4-di-N-oxides (QdNOs) are a class of bioreductive compounds, however, their antibacterial mechanisms are still unclarified. The aim of this study was to assess the ability of two representative QdNO drugs, cyadox (CYA) and olaquindox (OLA), to produce reactive oxide species (ROS) in Gram-positive anaerobe Clostridium perfringens CVCC1125 and Gram-negative anaerobe Brachyspira hyodysenteriae B204. In addition, the effects of QdNOs on the integrity of bacterial cell walls and membranes as well as the morphological alterations and DNA oxidative damage in C. perfringens and B. hyodysenteriae were analyzed. It was demonstrated that under anaerobic conditions, QdNOs were metabolized into the reduced products which did not show any antibacterial activity. A significant dose-related increase of intracellular ROS level and intracellular hydroxyl radicals were evident in bacteria exposed to QdNOs. The result of biochemical assay showed that the cell walls and membranes of the bacteria treated with QdNOs were damaged. After exposure to 1/2MIC to 4MIC of CYA and OLA, C. perfringens and B. hyodysenteriae became elongated and filamentous. Morphological observation with scanning and transmission electron microscopes revealed rupture, loss of cytoplasmic material and cell lysis in QdNO-treated bacteria, indicating serious damage of cells. There was an increase of 8-OHdG in the two strains treated by QdNOs, but it was lower in C. perfringens CVCC1125 than in B. hyodysenteriae B204. Agarose gel electrophoresis showed the degradation of chromosomal DNA in both of the two anaerobes treated by QdNOs. The results suggest that QdNOs may kill C. perfringens and B. hyodysenteriae via the generation of ROS and hydroxyl radicals from the bacterial metabolism of QdNOs, which cause oxidative damage in bacteria under anaerobic conditions.
Highlights
MATERIALS AND METHODSQuinoxaline 1,4-di-N-oxide derivatives (QdNOs), including carbadox, OLA, mequindox, quinocetone, and CYA, are a class of synthetic heterocycles that are known as potent antibacterial agents against many Gram-positive and Gram-negative bacteria, especially anaerobes
OLA was metabolized into olaquindox 4-monoxide (O1) and O2 in these two species under anaerobic conditions (Supplementary Figure S2), indicating that quinoxaline 1 (QdNOs) was mainly reduced at the two N-oxide groups on the quinoxaline ring
Quinoxaline 1,4-di-N-oxides belong to the heterocyclic family of benzodiazepine with its N–O groups situated at 1- and 4positions which are considered to contribute to antibacterial activities and other versatile abilities (Hennessey and Edwards, 1972; Cheng et al, 2016)
Summary
Quinoxaline 1,4-di-N-oxide derivatives (QdNOs), including carbadox, OLA, mequindox, quinocetone, and CYA, are a class of synthetic heterocycles that are known as potent antibacterial agents against many Gram-positive and Gram-negative bacteria, especially anaerobes. OLA, mequindox are commonly used as feed additives to prevent bacterial infectious disease and improve animal growth in livestock and poultry (Cheng et al, 2016). Clostridium perfringens is a Gram-positive spore-forming obligate anaerobe that causes food poisoning, gas gangrene, and antibiotic-associated diarrhea (Farzan et al, 2013; Uzal et al, 2014). C. perfringens with decreased susceptibility to metronidazole (Alvarez-Perez et al, 2016) was found to be sensitive to CYA and OLA in the study of our laboratory. Carbadox used to be added to feed or drinking water for the treatment of SD (Sabbatini, 2009)
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