Resistance risk induced by quorum sensing inhibitors and their combined use with antibiotics: Mechanism and its relationship with toxicity.

The abuse of antibiotics has brought out serious bacterial resistance, which threatens the ecological environment and human health. Quorum sensing inhibitors (QSIs), as a new kind of potential antibiotic substitutes that are theoretically difficult to trigger bacterial resistance, are recommended to individually use or jointly use with traditional antibiotics. However, there are few studies on the resistance risk in the use of QSIs. In this study, the influence of QSIs alone or in combination with sulfonamides (SAs) on conjugative transfer and mutation of Escherichia coli (E. coli) was investigated to explore whether QSIs have the potential to induce bacterial resistance. The results show that QSIs may facilitate plasmid RP4 conjugative transfer by binding with SdiA protein to regulate pilus expression, and interact with LsrR protein to increase SOS gene expression, inducing gene mutation. The QSIs-SAs mixtures could promote plasmid RP4 conjugative transfer and mutation in E. coli, and the main joint effects are synergism and antagonism. Furthermore, there is a good correlation among conjugative transfer, mutation, and growth inhibition of QSIs-SAs to E. coli. It could be speculated that bacteria may delay cell division to provide sufficient energy and time for regulating conjugative transfer and mutation under the stress of QSIs and their combined exposure with antibiotics, which is essentially a balance between bacterial resistance and toxicity. This study provides a reference for the resistance risk assessment of QSIs and benefits the clinical application of QSIs.