Type III Secretion-Dependent Sensitivity of Escherichia coli O157 to Specific Ketolides

• Published in: Antimicrobial agents and chemotherapy 2016-01, Vol.60 (1), p.459-470
• Main Authors: Fernandez-Brando, Romina J, Yamaguchi, Nao, Tahoun, Amin, McAteer, Sean P, Gillespie, Trudi, Wang, Dai, Argyle, Sally A, Palermo, Marina S, Gally, David L
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacterial Adhesion - drug effects; Caco-2 Cells; Cattle; Cell Line; Drug Discovery; Epithelial Cells - drug effects; Epithelial Cells - microbiology; Escherichia coli; Escherichia coli O157; Escherichia coli O157 - drug effects; Escherichia coli O157 - genetics; Escherichia coli O157 - metabolism; Gene Expression; High-Throughput Screening Assays; Humans; Ketolides; Ketolides - chemistry; Ketolides - pharmacology; Macrolides; Macrolides - chemistry; Macrolides - pharmacology; Microbial Sensitivity Tests; Respiratory Mucosa - drug effects; Respiratory Mucosa - microbiology; Small Molecule Libraries; Small Molecule Libraries - pharmacology; Susceptibility; Triazoles; Triazoles - chemistry; Triazoles - pharmacology; Type III Secretion Systems; Type III Secretion Systems - antagonists & inhibitors; Type III Secretion Systems - genetics; Type III Secretion Systems - metabolism
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02085-15

A subset of Gram-negative bacterial pathogens uses a type III secretion system (T3SS) to open up a conduit into eukaryotic cells in order to inject effector proteins. These modulate pathways to enhance bacterial colonization. In this study, we screened established bioactive compounds for any that could repress T3SS expression in enterohemorrhagic Escherichia coli (EHEC) O157. The ketolides telithromycin and, subsequently, solithromycin both demonstrated repressive effects on expression of the bacterial T3SS at sub-MICs, leading to significant reductions in bacterial binding and actin-rich pedestal formation on epithelial cells. Preincubation of epithelial cells with solithromycin resulted in significantly less attachment of E. coli O157. Moreover, bacteria expressing the T3SS were more susceptible to solithromycin, and there was significant preferential killing of E. coli O157 bacteria when they were added to epithelial cells that had been preexposed to the ketolide. This killing was dependent on expression of the T3SS. Taken together, this research indicates that the ketolide that has accumulated in epithelial cells may traffic back into the bacteria via the T3SS. Considering that neither ketolide induces the SOS response, nontoxic members of this class of antibiotics, such as solithromycin, should be considered for future testing and trials evaluating their use for treatment of EHEC infections. These antibiotics may also have broader significance for treating infections caused by other pathogenic bacteria, including intracellular bacteria, that express a T3SS.