Augmented dissemination of antibiotic resistance elicited by non-antibiotic factors

The emergence and rapid spread of antibiotic resistance seriously compromise the clinical efficacy of current antibiotic therapies, representing a serious public health threat worldwide. Generally, drug-susceptible bacteria can acquire antibiotic resistance through genetic mutation or gene transfer, among which horizontal gene transfer (HGT) plays a dominant role. It is widely acknowledged that the sub-inhibitory concentrations of antibiotics are the key drivers in promoting the transmission of antibiotic resistance. However, accumulating evidence in recent years has shown that in addition to antibiotics, non-antibiotics can also accelerate the horizontal transfer of antibiotic resistance genes (ARGs). Nevertheless, the roles and potential mechanisms of non-antibiotic factors in the transmission of ARGs remain largely underestimated. In this review, we depict the four pathways of HGT and their differences, including conjugation, transformation, transduction and vesiduction. We summarize non-antibiotic factors accounting for the enhanced horizontal transfer of ARGs and their underlying molecular mechanisms. Finally, we discuss the limitations and implications of current studies.