Novel Anti-Campylobacter Compounds Identified Using High Throughput Screening of a Pre-selected Enriched Small Molecules Library.
Campylobacter is a leading cause of foodborne bacterial gastroenteritis worldwide and infections can be fatal. The emergence of antibiotic-resistant Campylobacter spp. necessitates the development of new antimicrobials. We identified novel anti-Campylobacter small molecule inhibitors using a high throughput growth inhibition assay. To expedite screening, we made use of a "bioactive" library of 4182 compounds that we have previously shown to be active against diverse microbes. Screening for growth inhibition of Campylobacter jejuni, identified 781 compounds that were either bactericidal or bacteriostatic at a concentration of 200 μM. Seventy nine of the bactericidal compounds were prioritized for secondary screening based on their physico-chemical properties. Based on the minimum inhibitory concentration against a diverse range of C. jejuni and a lack of effect on gut microbes, we selected 12 compounds. No resistance was observed to any of these 12 lead compounds when C. jejuni was cultured with lethal or sub-lethal concentrations suggesting that C. jejuni is less likely to develop resistance to these compounds. Top 12 compounds also possessed low cytotoxicity to human intestinal epithelial cells (Caco-2 cells) and no hemolytic activity against sheep red blood cells. Next, these 12 compounds were evaluated for ability to clear C. jejuni in vitro. A total of 10 compounds had an anti-C. jejuni effect in Caco-2 cells with some effective even at 25 μM concentrations. These novel 12 compounds belong to five established antimicrobial chemical classes; piperazines, aryl amines, piperidines, sulfonamide, and pyridazinone. Exploitation of analogs of these chemical classes may provide Campylobacter specific drugs that can be applied in both human and animal medicine.
Food Animal Health Research Program, Department of Veterinary Preventive Medicine, The Ohio State UniversityWooster, OH, USA; Poultry CRC, University of New EnglandArmidale, NSW, Australia.
Anand
A
Kumar
Food Animal Health Research Program, Department of Veterinary Preventive Medicine, The Ohio State UniversityWooster, OH, USA; Poultry CRC, University of New EnglandArmidale, NSW, Australia.
Mary
M
Drozd
Food Animal Health Research Program, Department of Veterinary Preventive Medicine, The Ohio State University Wooster, OH, USA.
Ruby
R
Pina-Mimbela
Department of Plant Pathology, Ohio Agricultural Research and Development Center, The Ohio State University Wooster, OH, USA.
Xiulan
X
Xu
Food Animal Health Research Program, Department of Veterinary Preventive Medicine, The Ohio State University Wooster, OH, USA.
Yosra A
YA
Helmy
College of Pharmacy, The Ohio State University Columbus, OH, USA.
Janet
J
Antwi
College of Pharmacy, The Ohio State University Columbus, OH, USA.
James R
JR
Fuchs
Pharmaceutical Sciences, The University of British Columbia Vancouver, BC, Canada.
Corey
C
Nislow
Department of Agriculture and Fisheries, EcoSciences Precinct Dutton Park, QLD, Australia.
Jillian
J
Templeton
Poultry CRC, University of New EnglandArmidale, NSW, Australia; Queensland Alliance for Agriculture and Food Innovation, The University of Queensland, EcoSciences PrecinctDutton Park, QLD, Australia.
Patrick J
PJ
Blackall
Food Animal Health Research Program, Department of Veterinary Preventive Medicine, The Ohio State University Wooster, OH, USA.
Gireesh
G
Rajashekara
Campylobacter; enriched small molecules library; food safety; high throughput screening; small molecules