Specific ketolides demonstrate increased cytotoxicity for E. coli O157 strains expressing a type 3 secretion system and inhibit expression of the system at sub-minimum inhibitory concentrations.

SP MCATEER; R FERNÁNDEZ-BRANDO; N YAMAGUCHI; A TAHOUN,; MS PALERMO; S ARGYLE; DL. GALLY

Boston

Congreso; 9th International Symposium on Shiga toxin (Verocytotoxin) producing Escherichia coli Infections (VTEC2012),; 2015

VTEC

A subset of Gram negative bacterial pathogens use atype 3 secretion system (T3SS) to open up a conduit into eukaryotic cells inorder to inject effector proteins.  Thesemodulate pathways to enhance bacterial colonization. In this study we screenedestablished bioactive compounds for any that could repress T3SS expression inenterohemorrhagic Escherichia coli(EHEC) O157. The ketolides, Telithromycin and subsequently solithromycin both demonstratedrepressive effects on expression of the bacterial T3SS at sub-minimuminhibitory (sub-MIC) concentrations, leading to significant reductions inbacterial binding and actin-rich pedestal formation on epithelial cells.  Pre-incubation of epithelial cells withsolithromycin resulted in significantly less attachment of E. coli O157.  Moreover,bacteria expressing the T3SS were more susceptible to solithromycin and therewas significant preferential killing of E.coli O157 when added to epithelial cells pre-exposed to the ketolide. Thiskilling was dependent on expression of the T3SS. Taken together, this researchindicates that the ketolide may traffic back into the bacteria via the T3SSfrom accumulated levels in epithelial cells. Considering that neither ketolide induces the SOS response, non-toxicmembers of this class of antibiotic, such as solithromycin, should be consideredfor future testing and trials in relation to EHEC infections. These antibioticsmay also have broader significance for treating other pathogenic bacteria,including intracellular bacteria, that express a T3SS.