Novel anti-campylobacter compounds identified using high throughput screening of a pre-selected enriched small molecules library

Kumar, Anand, Drozd, Mary, Pina-Mimbela, Ruby, Xu, Xiulan, Helmy, Yosra A., Antwi, Janet, Fuchs, James R., Nislow, Corey, Templeton, Jillian, Blackall, Patrick J. and Rajashekara, Gireesh (2016) Novel anti-campylobacter compounds identified using high throughput screening of a pre-selected enriched small molecules library. Frontiers in Microbiology, 7 APR: 405. doi:10.3389/fmicb.2016.00405


Author Kumar, Anand
Drozd, Mary
Pina-Mimbela, Ruby
Xu, Xiulan
Helmy, Yosra A.
Antwi, Janet
Fuchs, James R.
Nislow, Corey
Templeton, Jillian
Blackall, Patrick J.
Rajashekara, Gireesh
Title Novel anti-campylobacter compounds identified using high throughput screening of a pre-selected enriched small molecules library
Journal name Frontiers in Microbiology   Check publisher's open access policy
ISSN 1664-302X
Publication date 2016-04-06
Year available 2016
Sub-type Article (original research)
DOI 10.3389/fmicb.2016.00405
Open Access Status DOI
Volume 7
Issue APR
Start page 405
Total pages 12
Place of publication Lausanne, Switzerland
Publisher Frontiers Research Foundation
Language eng
Subject 2404 Microbiology
2726 Microbiology (medical)
Abstract 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.
Formatted abstract
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.
Keyword Campylobacter
Anti-Campylobacter compounds
Small molecules library
Foodborne bacterial gastroenteritis
Antibiotic resistant
Antimicrobials
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 2012-68003-19679
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Alliance for Agriculture and Food Innovation
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 2 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 3 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Sun, 01 May 2016, 10:18:36 EST by System User on behalf of Learning and Research Services (UQ Library)