Targeting Plasmid Conjugation with Cinnamic Acid: A Novel Approach to Combat Antibiotic Resistance

The global spread of antibiotic resistance genes (ARGs) continues to worsen, with plasmid-mediated conjugation serving as a major transmission route. Although developing conjugation inhibitors to block this process is a promising strategy, current options are limited by toxicity and poor in vivo efficacy. This study evaluated the effect of cinnamic acid (CA; 3-phenyl-2-acrylic acid), a widely abundant food additive found in cinnamon, on plasmid conjugation. CA effectively inhibited the conjugation of various resistance plasmids in vitro, ex vivo, and in vivo. Transcriptomic analysis indicated that CA disrupts the electron transport chain (ETC) and proton motive force (PMF) by inhibiting the tricarboxylic acid (TCA) cycle, leading to reduced intracellular adenosine triphosphate (ATP)—a critical factor for plasmid conjugation. Biocompatibility assays showed that CA maintains high biosafety while preserving gut microbiota homeostasis. Therefore, these findings provide new insights into ARG inhibition and highlight the potential of CA as a novel strategy to combat the global rise in antibiotic-resistant infections.