Rationally Designed Pyrimidine Compounds: Promising Novel Antibiotics for the Treatment of Staphylococcus aureus-Associated Bovine Mastitis
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Published:2023-08-21
Issue:8
Volume:12
Page:1344
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ISSN:2079-6382
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Container-title:Antibiotics
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language:en
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Short-container-title:Antibiotics
Author:
Millette Guillaume1ORCID, Lacasse Evelyne1, Binette Renaud2ORCID, Belley Véronique1, Chaumont Louis-Philippe1, Ster Céline1ORCID, Beaudry Francis3, Boyapelly Kumaraswamy4, Boudreault Pierre-Luc4ORCID, Malouin François1ORCID
Affiliation:
1. Department of Biology, Institute of Sciences, University of Sherbrooke, Sherbrooke, QC J1K 2R1, Canada 2. Department of Chemistry, Institute of Sciences, University of Sherbrooke, Sherbrooke, QC J1K 2R1, Canada 3. Department of Veterinary Biomedicine, Institute of Veterinary Medicine, University of Montreal, St-Hyacinthe, QC J2S 2M2, Canada 4. Department of Pharmacology and Physiology, Institute of Medicine and Health Sciences, Sherbrooke University, Sherbrooke, QC J1H 5N4, Canada
Abstract
Staphylococcus aureus is one of the major pathogens causing bovine mastitis, and antibiotic treatment is most often inefficient due to its virulence and antibiotic-resistance attributes. The development of new antibiotics for veterinary use should account for the One Health concept, in which humans, animals, and environmental wellbeing are all interconnected. S. aureus can infect cattle and humans alike and antibiotic resistance can impact both if the same classes of antibiotics are used. New effective antibiotic classes against S. aureus are thus needed in dairy farms. We previously described PC1 as a novel antibiotic, which binds the S. aureus guanine riboswitch and interrupts transcription of essential GMP synthesis genes. However, chemical instability of PC1 hindered its development, evaluation, and commercialization. Novel PC1 analogs with improved stability have now been rationally designed and synthesized, and their in vitro and in vivo activities have been evaluated. One of these novel compounds, PC206, remains stable in solution and demonstrates specific narrow-spectrum activity against S. aureus. It is active against biofilm-embedded S. aureus, its cytotoxicity profile is adequate, and in vivo tests in mice and cows show that it is effective and well tolerated. PC206 and structural analogs represent a promising new antibiotic class to treat S. aureus-induced bovine mastitis.
Funder
Natural Sciences and Engineering Research Council Canadian Foundation for Innovation Canada Research Chair
Subject
Pharmacology (medical),Infectious Diseases,Microbiology (medical),General Pharmacology, Toxicology and Pharmaceutics,Biochemistry,Microbiology
Reference39 articles.
1. Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis;Murray;Lancet,2022 2. World Health Organization (2023, July 25). WHO Antibacterial Preclinical Pipeline Review. Available online: https://www.who.int/observatories/global-observatory-on-health-research-and-development/monitoring/who-antibacterial-preclinical-pipeline-review. 3. Antibiotics in the clinical pipeline as of December 2022;Butler;J. Antibiot.,2023 4. One Health High-Level Expert Panel (OHHLEP), Adisasmito, W.B., Almuhairi, S., Behravesh, C.B., Bilivogui, P., Bukachi, S.A., Casas, N., Becerra, N.C., Charron, D.F., and Chaudhary, A. (2022). One Health: A new definition for a sustainable and healthy future. PLoS Pathog., 18. 5. Antimicrobial Resistance: A One Health Perspective;McEwen;Microbiol. Spectr.,2018
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