B-157. Antibiotics with High Therapeutic Potential for the Treatment of E. coli O157:H7 Include Transcription and Translation Inhibitors

C. McGannon, A. Weiss;
Univ. of Cincinnati, Cincinnati, OH.

The food borne pathogen Escherichia coli O157:H7 produces Shiga toxin, a major cause of hemolytic uremic syndrome (HUS) development and death. Shiga toxin is encoded on a bacteriophage integrated into the E. coli O157:H7 genome, and is only produced during the viral lytic cycle. The lytic cycle is activated in vitro and in vivo by the presence of certain antibiotics including ciprofloxacin. Studies suggest that ciprofloxacin increases disease severity and the likelihood of developing HUS during E. coli O157:H7 infection. We are investigating whether antibiotics eliminate E. coli O157:H7 without increasing Shiga toxin production using clinical isolates of E. coli O157:H7. The macrobroth dilution assay was used to determine the minimum inhibitory concentration of antibiotics commonly used to treat infectious diarrhea. Clinical isolates of E. coli O157:H7 were inoculated into serial dilutions of antibiotic and incubated overnight. Production of biologically active Shiga toxin was measured by monitoring inhibition of protein synthesis via the reduction of luciferase in a Vero cell line. As previously observed, subinhibitory concentrations of ciprofloxacin induced Shiga toxin production, up to 23-fold in log phase cells. Trimethoprim/sulfamethoxazole was observed to induce Shiga toxin production up to 63-fold. Importantly, several antibiotics did not induce Shiga toxin production. Incubation in ampicillin, ceftriaxone, gentamicin, and rifampicin yielded basal levels of toxin. Most interesting, some antibiotics reduced Shiga toxin production; fosfomicin, azithromicin and doxycycline reduced toxin production by 5- to 37-fold. In summary, these studies have shown that antibiotics that target DNA (ciprofloxacin) or metabolic processes (trimethoprim/sulfamethoxazole) may not be safe for the treatment of E. coli O157:H7 infection. However, antibiotics that target transcription and translation are potential therapeutic candidates for treatment of E. coli O157:H7 infection.