Novel narrow spectrum benzyl thiophene sulfonamide derivatives to control Campylobacter

Campylobacter is a leading cause of bacterial foodborne gastroenteritis worldwide, and poultry are a major source of human campylobacteriosis. The control of Campylobacter from farm to fork is challenging due to emergence of microbial resistance and lack of effective control methods. We identified a benzyl thiophene sulfonamide based small molecule (compound 1) with a minimal inhibitory concentration (MIC) of 100 mu M against Campylobacter jejuni 81-176 and Campylobacter coli ATCC33559, good drug-like properties, and low toxicity on eukaryotic cells. Compound 1 was used as a lead for the preparation of 13 analogues. Two analogues, compounds 4 and 8 (TH-4 and TH-8), were identified with better antimicrobial properties than compound 1. TH-4 and TH-8 had a MIC of 12.5 mu M and 25 mu M for C. coli and 50 mu M and 100 mu M for C. jejuni, respectively. Cytological studies revealed that both compounds affected C. jejuni envelope integrity. Further, both compounds had no effect on other foodborne pathogens. TH-4 and TH-8 had a minimal impact on the chicken cecal microbiota and were not toxic to colon epithelial cells and chicken macrophages, and red blood cells at 200 mu M. Further, TH-4 and TH-8 reduced the Campylobacter load in chicken ceca (up to 2-log reduction) when infected chickens were orally treated for 5 days with 0.254 mg kg(-1); as well as against internalized Campylobacter in Caco-2 cells at 12.5 mu M and higher. Our study identified two novel specific and safe benzyl thiophene sulfonamide derivatives having potential for control of Campylobacter in chickens and humans.