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 th...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2016-04-01
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| Series: | Frontiers in Microbiology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fmicb.2016.00405/full |
| _version_ | 1828369397123645440 |
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| author | Anand eKumar Mary eDrozd Ruby ePina-Mimbela Xiulan eXu Yosra A Helmy Janet eAntwi James R Fuchs Corey eNislow Jillian eTempleton Patrick J Blackall Gireesh eRajashekara |
| author_facet | Anand eKumar Mary eDrozd Ruby ePina-Mimbela Xiulan eXu Yosra A Helmy Janet eAntwi James R Fuchs Corey eNislow Jillian eTempleton Patrick J Blackall Gireesh eRajashekara |
| author_sort | Anand eKumar |
| collection | DOAJ |
| description | 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 4,182 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 analogues of these chemical classes may provide Campylobacter specific drugs that can be applied in both human and animal medicine. |
| first_indexed | 2024-04-14T06:23:29Z |
| format | Article |
| id | doaj.art-68c911ff88774583972760b2f099913c |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-04-14T06:23:29Z |
| publishDate | 2016-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-68c911ff88774583972760b2f099913c2022-12-22T02:07:56ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2016-04-01710.3389/fmicb.2016.00405183792Novel anti-campylobacter compounds identified using high throughput screening of a pre-selected enriched small molecules libraryAnand eKumar0Mary eDrozd1Ruby ePina-Mimbela2Xiulan eXu3Yosra A Helmy4Janet eAntwi5James R Fuchs6Corey eNislow7Jillian eTempleton8Patrick J Blackall9Gireesh eRajashekara10The Ohio State UniversityThe Ohio State UniversityThe Ohio State UniversityThe Ohio State UniversityThe Ohio State UniversityThe Ohio State UniversityThe Ohio State UniversityUniversity of British ColumbiaDepartment of Agriculture and FisheriesThe University of QueenslandThe Ohio State UniversityCampylobacter 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 4,182 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 analogues of these chemical classes may provide Campylobacter specific drugs that can be applied in both human and animal medicine.http://journal.frontiersin.org/Journal/10.3389/fmicb.2016.00405/fullCampylobacterFood Safetyantibiotic resistancesmall moleculesHigh throughput screeningenriched small molecules library |
| spellingShingle | Anand eKumar Mary eDrozd Ruby ePina-Mimbela Xiulan eXu Yosra A Helmy Janet eAntwi James R Fuchs Corey eNislow Jillian eTempleton Patrick J Blackall Gireesh eRajashekara Novel anti-campylobacter compounds identified using high throughput screening of a pre-selected enriched small molecules library Frontiers in Microbiology Campylobacter Food Safety antibiotic resistance small molecules High throughput screening enriched small molecules library |
| title | Novel anti-campylobacter compounds identified using high throughput screening of a pre-selected enriched small molecules library |
| title_full | Novel anti-campylobacter compounds identified using high throughput screening of a pre-selected enriched small molecules library |
| title_fullStr | Novel anti-campylobacter compounds identified using high throughput screening of a pre-selected enriched small molecules library |
| title_full_unstemmed | Novel anti-campylobacter compounds identified using high throughput screening of a pre-selected enriched small molecules library |
| title_short | Novel anti-campylobacter compounds identified using high throughput screening of a pre-selected enriched small molecules library |
| title_sort | novel anti campylobacter compounds identified using high throughput screening of a pre selected enriched small molecules library |
| topic | Campylobacter Food Safety antibiotic resistance small molecules High throughput screening enriched small molecules library |
| url | http://journal.frontiersin.org/Journal/10.3389/fmicb.2016.00405/full |
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