The global spread of antibiotic resistance has posed a serious threat to public 
healthcare and undermined decades of progress made in the fight against 
bacterial infections. It has been demonstrated that the lack of novel effective 
antibiotics and rapid spread of antibiotic resistance genes via horizontal 
transfer in the ecosystem are mainly responsible for this crisis. Notably, 
plasmid-mediated horizontal transfer of antibiotic resistance genes (ARGs) is 
recognized as the most dominant dissemination pathway of ARGs in humans, animals 
and environmental settings. Antibiotic selective pressure has always been 
regarded as one of the crucial contributors to promoting the dissemination of 
antibiotic resistance through horizontal gene transfer (HGT). However, the roles 
of exogenous compounds and particularly non-antibiotic drugs in the spread of 
ARGs are still underappreciated. In this review, we first summarize the major 
pathways of HGT in bacteria, including conjugation, transformation, transduction 
and vesiduction. Subsequently, an overview of these compounds capable of 
promoting the HGT is presented, which guides to the formulation of more 
reasonable dosing regimens and drug residue standards in clinical practice. By 
contrast, these compounds that display an inhibition effect on HGT are also 
highlighted, which provides a unique strategy to minimize the spread of ARGs. 
Lastly, we discuss the implementations and challenges in bringing these HGT 
inhibitors into clinical trials.