Inducibility of Tn916 conjugative transfer in Enterococcus faecalis by subinhibitory concentrations of ribosome-targeting antibiotics.

Background: Some antibiotics induce the dissemination of their own resistance genes by interfering with the regulation of specific mobile genetic elements. In Tn916, subinhibitory concentrations of tetracycline activate the transfer of the element through an anti-attenuation mechanism that relies on the Tet(M) resistance protein, itself encoded by the element. Objectives: This work explores the effects of a broad range of antibiotics on the transfer of Tn916 and for which the element does not provide any selective advantage. Methods: A sensitive promoter-reporter fusion approach was developed to test the effects of full antibiotic concentration gradients on gene promoter expression. Sixty molecules, covering most classes of antibiotics, were screened for their ability to modulate the activity of promoter Porf12 controlling the transfer of Tn916. Induction of Tn916 transfer was further demonstrated in mating assays with Enterococcus faecalis donors pre-exposed to subinhibitory concentrations of modulating antibiotics. Results: Several antibiotics, other than tetracyclines, were identified as interfering with Tn916 regulation. Macrolides, lincosamides and streptogramins appeared to activate the transfer of Tn916 at unprecedented levels, in a Tet(M)-independent way that implies a yet undescribed regulatory mechanism for controlling the mobility of the element. Conclusions: These results demonstrate that some ribosome-targeting antibiotics can induce the transfer of a given mobile genetic element, here Tn916, although it does not provide any resistance determinant for most of the triggering drugs. This implies that specific antibiotic therapies can have dramatic impacts on the dissemination of unexpected and unlinked resistance genes, with the clear risk of reducing our therapeutic potential for later treatments.