Evaluation of Novel Quorum Sensing Inhibitors Targeting Auto-Inducer 2 (AI-2) for the Control of Avian Pathogenic Escherichia coli Infections in Chickens

Yosra A. Helmy, Dipak Kathayat, Loic Deblais, Vishal Srivastava, Gary Closs, Robert J. Tokarski, Oluwatosin Ayinde, James R. Fuchs, Gireesh Rajashekara

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Avian pathogenic Escherichia coli (APEC) associated with colibacillosis results in high morbidity and mortality, and severe economic losses to the poultry industry. APEC is a zoonotic pathogen and can infect humans through contaminated poultry products. Vaccination and antibiotic treatment are currently used to control APEC infections; however, the limited effect of vaccines and the emergence of antibiotic-resistant strains have necessitated the development of novel therapeutics. Here, we evaluated seven quorum sensing inhibitors (QSI) identified in our previous study, in APEC-infected chickens. QSIs were administered orally (;92 to 120 mg/bird) and chickens were challenged subcutaneously with APEC. Among them, QSI-5 conferred the best protection (100% reduction in mortality, 82% to 93% reduction in lesions [airsacculitis, perihepatitis, lung congestion, pericarditis] severity, and 5.2 to 6.1 logs reduction in APEC load). QSI-5 was further tested in chickens raised on built-up floor litter using an optimized dose (1 mg/L) in drinking water. QSI-5 reduced the mortality (88.4%), lesion severity (72.2%), and APEC load (2.8 logs) in chickens, which was better than the reduction observed with currently used antibiotic sulfadimethoxine (SDM; mortality 35.9%; lesion severity up to 36.9%; and APEC load up to 2.4 logs). QSI-5 was detected in chicken's blood after 0.5 h with no residues in muscle, liver, and kidney. QSI-5 increased the body weight gain with no effect on the feed conversion ratio and cecal microbiota of the chickens. Metabolomic studies revealed reduced levels of 59-methylthioadenosine in QSI-5-treated chicken serum. In conclusion, QSI-5 displayed promising effects in chickens and thus, represents a novel anti-APEC therapeutic. IMPORTANCE Avian pathogenic Escherichia coli (APEC), a subgroup of ExPEC, is a zoonotic pathogen with public health importance. Quorum sensing is a mechanism that regulates virulence, biofilm formation, and pathogenesis in bacteria. Here, we identified a novel quorum sensing autoinducer-2 inhibitor, QSI-5, which showed higher anti-APEC efficacy in chickens compared to the currently used antibiotic, sulfadimethoxine at a much lower dose (up to 4,500 times). QSI-5 is readily absorbed with no residues in the tissues. QSI-5 also increased the chicken’s body weight gain and did not impact the cecal microbiota composition. Overall, QSI-5 represents a promising lead compound for developing novel anti-virulence therapies with significant implications for treating APEC infections in chickens as well as other ExPEC associated infections in humans. Further identification of its target(s) and understanding the mechanism of action of QSI-5 in APEC will add to the future novel drug development efforts that can overcome the antimicrobial resistance problem.

Original languageEnglish
JournalMicrobiology spectrum
Volume10
Issue number3
DOIs
StatePublished - Jun 2022

Bibliographical note

Funding Information:
We thank Wilbur Ouma for the assistance with the bioinformatic analysis. We thank Matthew Bernier for the assistance with the metabolomic analysis. We thank Juliette Hanson, Megan Strother, and Sara Tallmadge for assistance with chicken experiments. The research in Rajashekara laboratory is supported by the U.S. Department of Agriculture (USDA), National Institute for Food and Agriculture (NIFA) (grants number 2015-68004-23131 and 2020-6701-31401), the Technology Commercialization Office (TCO) of The Ohio State University, and the Ohio State Innovation Foundation. We declare no competing interests.

Publisher Copyright:
Copyright © 2022 Helmy et al.

Keywords

  • 5'-methylthioadenosine
  • anti-virulence
  • APEC
  • auto-inducer 2
  • chickens
  • inhibitors
  • QSI-5
  • quorum sensing
  • sulfadimethoxine

ASJC Scopus subject areas

  • Physiology
  • Ecology
  • Immunology and Microbiology (all)
  • Genetics
  • Microbiology (medical)
  • Cell Biology
  • Infectious Diseases

Fingerprint

Dive into the research topics of 'Evaluation of Novel Quorum Sensing Inhibitors Targeting Auto-Inducer 2 (AI-2) for the Control of Avian Pathogenic Escherichia coli Infections in Chickens'. Together they form a unique fingerprint.

Cite this