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Title
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Elucidation of the clinical relevance and potential mechanisms of persistence in Streptococcus pneumoniae
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Author
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Abstract
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| Infectious diseases exist already for millennia and so does antimicrobial therapy. The past 100 years, major advances were accomplished into the fight against infectious diseases, especially with the discovery of antimicrobial agents. Unfortunately, these discoveries were accompanied with the fast emergence of antimicrobial resistance. Many efforts were made regarding research into antimicrobial resistance, but bacteria can evade antibiotic treatment also in different ways resulting in therapy failure. One way of how bacteria can evade killing by antibiotics, regardless of resistance, is antibiotic persistence. Persister cells are phenotypic variants that exist as a subpopulation within a clonal culture and can transiently switch to a nongrowing state that enables them to survive treatment with a bactericidal drug concentration. Being tolerant to lethal antibiotics, they underly the chronic nature of a variety of infections and even help in acquiring genetic resistance. Streptococcus pneumoniae is a common colonizer of the mucosal surfaces of the nasopharynx of children, but can also cause life-threating diseases like pneumonia, sepsis and meningitis. S. pneumoniae remains a major cause of morbidity and mortality worldwide, despite the availability of a vaccine, and is classified as a priority pathogen by the World Health Organization (WHO) in 2024 for the need of novel antibiotics. Many reports were published about antibiotic persistence in a variety of bacterial species, but for Streptococcus pneumoniae, no studies were published. We were the first to report the presence of persisters in S. pneumoniae cultures for different clinically relevant, bactericidal antibiotics (amoxicillin, cefuroxime, moxifloxacin and vancomycin) using our optimized long-living in vitro model. We detected high persister levels for S. pneumoniae reference strain D39 varying according to the growth phase and the antibiotic. Experimental evolution did not lead to the formation of a highly persistent phenotype which hampered us to investigate the molecular mechanisms behind S. pneumoniae persistence. Furthermore, we employed a large set of S. pneumoniae clinical isolates to prove the clinical relevance of S. pneumoniae persistence as persister cells were widely present in our strain collection. Finally, we made the first steps for the optimization of a long-term in vivo model to enable persistence studies in a clinically relevant setting. Altogether, our work advocates for higher interest for persistence in S. pneumoniae as a contributing factor for therapy failure and resistance development. |
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Language
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English
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Publication
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Antwerp
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University of Antwerp, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Department of Pharmaceutical Sciences
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2024
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DOI
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10.63028/10067/2105560151162165141
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Volume/pages
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xxiv, 237 p.
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Note
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Cos, Paul [Supervisor]
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Bergh, Van den, Bram [Supervisor]
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Full text (open access)
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