Electron transport chain: a crucial target of luteolin in combating Trueperella pyogenes

ABSTRACT Trueperella pyogenes is an opportunistic pathogen capable of causing infections in both domestic and wild animals. Furthermore, the dissemination of resistance genes has resulted in varying degrees of antimicrobial resistance among T. pyogenes isolates. Therefore, it is necessary to develop new anti- T . pyogenes drugs to address its increasing resistance. Luteolin, a natural flavonoid, has been found to exhibit good antibacterial activity against T. pyogenes in our previous research. This study aims to utilize high-throughput proteomics technology to identify potential novel targets and illuminate the action mechanism of luteolin. Our results indicated that luteolin could target electron transport chain complexes I, II, and V to inhibit the oxidative phosphorylation of T. pyogenes . Besides, luteolin could inhibit the enzyme activities involved in glycolysis and the tricarboxylic acid cycle, which eventually leads to a decrease in reduced hydrogen supplied to the electron transport chain and reduces the content of intracellular adenosine triphosphate. Based on the high-throughput proteomic analysis and multiple experimental results, the inhibition of electron transport chain complexes appears to be a significant mechanism by which luteolin exerts its antibacterial effect against T. pyogenes . Overall, this study provides a new insight into the anti- T . pyogenes mechanism of luteolin and offers new targets to develop anti- T . pyogenes drugs. IMPORTANCE Trueperella pyogenes is an opportunistic pathogen that can cause suppurative infections in multiple animals. Its existing resistance may bring challenges to anti-infection therapy. As a promising natural antibacterial agent, luteolin shows potent activity against this bacterium. This study revealed that luteolin disrupts bacterial energy metabolism by targeting electron transport chain complexes, thereby reducing intracellular adenosine triphosphate content. Our findings expanded the new antibacterial mechanism of luteolin and identified novel targets. This work provides valuable references for developing novel drugs against drug-resistant bacterial infections by targeting the electron transport chain.