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Tackling difficult-to-treat Staphylococcus aureus infections

English title Tackling difficult-to-treat Staphylococcus aureus infections
Applicant Zinkernagel Annelies
Number 204343
Funding scheme Project funding (Div. I-III)
Research institution Infektiologie Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Experimental Microbiology
Start/End 01.12.2021 - 30.11.2025
Approved amount 959'087.00
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All Disciplines (3)

Discipline
Experimental Microbiology
Pathophysiology
Medical Microbiology

Keywords (6)

persistent infection; Staphylococcus aureus; antibiotic persistence; Difficult-to-treat infections; Bacterial persisters; Antibiotic tolerance

Lay Summary (German)

Lead
Auf den Spuren von schwer zu behandelnden Staphylococcus aureus Infektionen
Lay summary
Infektionen, die trotz adäquater Antbiotikatherapie, nicht erfolgreich behandelt werden können, stellen eine grosse Last für das Gesundheitssystem dar und sind mit schlechter Lebensqualität und hoher Mortalität assoziiert. Staphylococcus aureus ist ein Bakterium, das oft solche schwer zu behandelnde Infektionen verursacht, auch wenn es zur normalen bakteriellen Flora der Nase und Haut gehört. 
Die Fähigkeit von Bakterien eine Antibiotikabehandlung zu überleben ohne jedoch resistent zu sein, wird als Antibiotikatoleranz beschrieben. Dieses Phänomen spielt eine wichtige Rolle bei schwer zu behandelnden Infekten. Bisher ist wenig darüber bekannt, wie sich eine solche Toleranz entwickeln und zu persistierenden Bakterien führen kann. 
Der Forschungsplan legt den Fokus auf das Entdecken der Mechanismen, die es S. aureus erlauben, eine lang andauernde Antibiotikabehandung zu überleben und auf die Interaktionen zwischen dem menschlichen Immunsystem und dem Pathogen. Weiter wird nach neuen Strategien gesucht, um persistierende Bakterien zu bekämpfen. 
Direct link to Lay Summary Last update: 14.10.2021

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
184918 Personalized Medicine in cardiovascular infections 01.04.2019 Project funding (Div. I-III)
180541 NCCR AntiResist (phase I) 01.08.2020 National Centres of Competence in Research (NCCRs)
176252 Staphylococcus aureus - persisting bacteria that are difficult to eradicate 01.10.2017 Project funding (Div. I-III)
167037 Novel targeted bacteriophage endolysin-based approach for treatment of drug-resistant Staphylococcus aureus infections 01.03.2017 NRP 72 Antimicrobial Resistance
185401 Infectious Diseases Biobank Zurich 01.03.2019 Biolink funds

Abstract

Staphylococcus aureus is an important human pathogen that colonizes up to 50% of the population and can cause a range of mild to life-threating infections. Chronic S. aureus infections are difficult-to-treat since the infections are not cleared despite treatment with adequate antibiotics and thus are a major clinical problem resulting in high morbidity and mortality. In addition, emergence of antibiotic resistance may evolve due to prolonged antibiotic therapy. Antibiotic resistance has been intensively studied and its underlying molecular mechanisms are mostly unraveled. On the other side, the phenomenon of susceptible bacteria with reduced metabolic activity that are able to survive high concentrations of antibiotics targeting actively growing bacteria has not been as extensively investigated. This phenomenon is described as antibiotic tolerance. A sub-population of these tolerant bacteria are hyper-tolerant and are described as persisters. The dynamics underlying antibiotic tolerance and bacterial persistence remain elusive and their study might provide novel options for difficult-to-treat infections.S. aureus persisters are characterized by a prolonged lag-time before growth resumption, resulting in a heterogeneous colony phenotype and in the appearance of non-stable small colonies (nsSCs) (1, 2). The lack of understanding the mechanisms triggering and regulating the appearance of persisters leave a knowledge gap that we plan to address with a translational approach.In this proposal, we aim to further characterize the phenomenon of S. aureus persistence in a clinically relevant setting by the use of experimental models dynamically mimicking the bacterial environment during an infection. We plan to focus on dissecting the molecular mechanisms of antibiotic persistence in S. aureus, in particular the roles of serine/threonine phosphorylation and chaperones in this process. We also aim to characterize phenotypic changes as a stress adaptation mechanism in S. aureus persisters during infection. Additionally, we will go further and integrate our knowledge on the mechanisms of persistence with the use of novel molecules for effectively tackling difficult-to-treat S. aureus infections by evaluating the efficacy of novel therapeutic molecules for eradicating persisters including retinoic acid derivatives, antimicrobial peptides, and hepcidin alone or in combination with standard antibiotics.We will utilize in vitro, in vivo and ex vivo infection models, microfluidics and real-time microscopy to monitor persisters’ behavior in response to stress at the single-cell level. Moreover, the molecular signature of persister populations will be analyzed via persister enrichment followed by broad-spectrum proteomics and transcriptomics analysis. We have access to a broad range of S. aureus clinical isolates as well as fresh samples collected from patients suffering from staphylococcal infections. Coupling these clinical samples with the development of assays mimicking the physiological environment the bacteria encounter during the infection process will allow to considerably advance the field of persister research. Up to now, this type of research has been mainly carried out using standard laboratory conditions and strains. The study of S. aureus persisters and their mechanisms should unravel currently unknown mechanisms by which bacteria survive antibiotics and will hopefully provide novel treatment targets.
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