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Staphylococcus aureus - persisting bacteria that are difficult to eradicate

English title Staphylococcus aureus - persisting bacteria that are difficult to eradicate
Applicant Zinkernagel Annelies
Number 176252
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 01.10.2017 - 30.09.2020
Approved amount 503'116.00
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All Disciplines (2)

Discipline
Experimental Microbiology
Immunology, Immunopathology

Keywords (6)

Staphylococcus aureus ; small colony variants ; chronic and recurrent infection; bacterial persistence; persisters; intracellular bacteria

Lay Summary (German)

Lead
Staphylococcus aureus - Persisters: schwierig zu eradizierende Bakterien
Lay summary

 

Chronische und wiederkehrende Infektionen durch Bakterien sind auch heutzutage ein substantielles und noch immer ungelöstes Problem. Trotz adäquater Antibiotikatherapie kommt es zu chronischen und wiederkehrenden Infektionen. Dies auch wenn die Bakterien gut empfindlich auf Antibiotika sind und eine resistenzgerechte optimale Antibiotikabehandlung erfolgt. Die Bakterien, die nicht resistent, sondern tolerant gegenüber Antibiotika sind, befinden sich in einem Ruhezustand, in dem sie sich nicht teilen und werden Persister genannt. Dadurch sind sie vor Antibiotika, die in einem aktiven Zellprozess wie der DNA-Replikation, Zellwand- und Proteinsynthese interferieren, geschützt. Sie können jedoch, sobald gewisse Stressoren wegfallen, wieder wachsen wodurch es zu einem Wiederauflammen der Infektion kommt. Die Charakterisierung persistierender Bakterien ist schwierig, da alle klassischen Bakterienanalysen auf Bakterienwachstum basieren. Staphylococcus aureus ist eines der häufigst isolierten Bakterien verantwortlich fuer viele klinisch relevant Infektionen.

Mithilfe eines automatisierten Agarplatten-Abbildungssystem sowie Zeitraffermikroskopie auf Basis von einzelnen Zellen werden wir die Wachstumskinetik von S. aureus charakterisieren. Wir werden die genetischen wie auch die Umweltfaktoren untersuchen, indem wir klinische Isolate aus akuten und chronischen Infekten verwenden.

Ein besseres Verständnis von persistierenden Bakterien wird einen signifikanten Einfluss auf die Gesundheit der betroffenen Patienten haben. Durch dieses Projekt werden wir neue Einblicke in die Interaktionen zwischen Wirt und Pathogen insbesondere Persister haben. Dies soll helfen, die Antibiotikabehandlungen anzupassen. Dieses Projekt hat daher das Potential, einen direkten Einfluss auf die klinische Praxis zu haben, indem neue Angriffsziele für Antibiotika und/oder antimikrobielle Therapien mit erhöhter Effizienz gefunden werden. Somit könnte die Dauer der Antibiotikabehandlung als auch die Therapiekosten gesenkt werden. 

Direct link to Lay Summary Last update: 23.10.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
Efficient microbial colony growth dynamics quantification with ColTapp, an automated image analysis application
Bär Julian, Boumasmoud Mathilde, Kouyos Roger D., Zinkernagel Annelies S., Vulin Clément (2020), Efficient microbial colony growth dynamics quantification with ColTapp, an automated image analysis application, in Scientific Reports, 10(1), 16084-16084.
Engineering of Long-Circulating Peptidoglycan Hydrolases Enables Efficient Treatment of Systemic Staphylococcus aureus Infection
Sobieraj Anna M., Huemer Markus, Zinsli Léa V., Meile Susanne, Keller Anja P., Röhrig Christian, Eichenseher Fritz, Shen Yang, Zinkernagel Annelies S., Loessner Martin J., Schmelcher Mathias (2020), Engineering of Long-Circulating Peptidoglycan Hydrolases Enables Efficient Treatment of Systemic Staphylococcus aureus Infection, in mBio, 11(5), x.
Polyester Vascular Graft Material and Risk for Intracavitary Thoracic Vascular Graft Infection1
Schweizer Tiziano A., Shambat Srikanth Mairpady, Haunreiter Vanina Dengler, Mestres Carlos A., Weber Alberto, Maisano Francesco, Zinkernagel Annelies S., Hasse Barbara (2020), Polyester Vascular Graft Material and Risk for Intracavitary Thoracic Vascular Graft Infection1, in Emerging Infectious Diseases, 26(10), 2448-2452.
Intracellular Environment and agr System Affect Colony Size Heterogeneity of Staphylococcus aureus
Häffner Nicola, Bär Julian, Dengler Haunreiter Vanina, Mairpady Shambat Srikanth, Seidl Kati, Crosby Heidi A., Horswill Alexander R., Zinkernagel Annelies S. (2020), Intracellular Environment and agr System Affect Colony Size Heterogeneity of Staphylococcus aureus, in Frontiers in Microbiology, 11, 1.
Targeting Hidden Pathogens: Cell-Penetrating Enzybiotics Eradicate Intracellular Drug-Resistant Staphylococcus aureus
Röhrig Christian, Huemer Markus, Lorgé Dominique, Luterbacher Samuel, Phothaworn Preeda, Schefer Christopher, Sobieraj Anna M., Zinsli Léa V., Mairpady Shambat Srikanth, Leimer Nadja, Keller Anja P., Eichenseher Fritz, Shen Yang, Korbsrisate Sunee, Zinkernagel Annelies S., Loessner Martin J., Schmelcher Mathias (2020), Targeting Hidden Pathogens: Cell-Penetrating Enzybiotics Eradicate Intracellular Drug-Resistant Staphylococcus aureus, in mBio, 11(2), x.
Epidermal hepcidin is required for neutrophil response to bacterial infection
Malerba Mariangela, Louis Sabine, Cuvellier Sylvain, Mairpady Shambat Srikanth, Hua Camille, Gomart Camille, Fouet Agnès, Ortonne Nicolas, Decousser Jean-Winoc, Zinkernagel Annelies S., Mathieu Jacques R.R., Peyssonnaux Carole (2019), Epidermal hepcidin is required for neutrophil response to bacterial infection, in Journal of Clinical Investigation, 0.
Definitions and guidelines for research on antibiotic persistence
Balaban Nathalie Q., Helaine Sophie, Lewis Kim, Ackermann Martin, Aldridge Bree, Andersson Dan I., Brynildsen Mark P., Bumann Dirk, Camilli Andrew, Collins James J., Dehio Christoph, Fortune Sarah, Ghigo Jean-Marc, Hardt Wolf-Dietrich, Harms Alexander, Heinemann Matthias, Hung Deborah T., Jenal Urs, Levin Bruce R., Michiels Jan, Storz Gisela, Tan Man-Wah, Tenson Tanel, Van Melderen Laurence, et al. (2019), Definitions and guidelines for research on antibiotic persistence, in Nature Reviews Microbiology, 17(7), 441-448.
Human polyspecific immunoglobulin attenuates group A streptococcal virulence factor activity and reduces disease severity in a murine necrotizing fasciitis model
Tarnutzer A., Andreoni F., Keller N., Zürcher C., Norrby-Teglund A., Schüpbach R.A., Zinkernagel A.S. (2019), Human polyspecific immunoglobulin attenuates group A streptococcal virulence factor activity and reduces disease severity in a murine necrotizing fasciitis model, in Clinical Microbiology and Infection, 25(4), 512.e7-512.e13.
Antibiotics stimulate vesicles formation in Staphylococcus aureus in both Phage-Dependent and -Independent Fashions and via Different Routes.
Andreoni Federica, Toyofuku Masanori, Menzi Carmen, Kalawong Ratchara, Mairpady Shambat Srikanth, François Patrice, Zinkernagel Annelies S, Eberl Leo (2019), Antibiotics stimulate vesicles formation in Staphylococcus aureus in both Phage-Dependent and -Independent Fashions and via Different Routes., in Antimicrobial agents and chemotherapy, 63(2), 0.
In-host evolution of Staphylococcus epidermidis in a pacemaker-associated endocarditis resulting in increased antibiotic tolerance
Dengler Haunreiter Vanina, Boumasmoud Mathilde, Häffner Nicola, Wipfli Dennis, Leimer Nadja, Rachmühl Carole, Kühnert Denise, Achermann Yvonne, Zbinden Reinhard, Benussi Stefano, Vulin Clement, Zinkernagel Annelies S. (2019), In-host evolution of Staphylococcus epidermidis in a pacemaker-associated endocarditis resulting in increased antibiotic tolerance, in Nature Communications, 10(1), 1149-1149.
Prolonged bacterial lag time results in small colony variants that represent a sub-population of persisters.
Vulin Clément, Leimer Nadja, Huemer Markus, Ackermann Martin, Zinkernagel Annelies S (2018), Prolonged bacterial lag time results in small colony variants that represent a sub-population of persisters., in Nature communications, 9(1), 4074-4074.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Instituskolloquium Wintersemester 2019/2020 Individual talk A translational perspective of Gram positive bacterial infections 12.12.2019 Münster, Germany Zinkernagel Annelies;
Infektiologie St. Gallen Individual talk Chronisch rezidivierende Staphylokokken Infektionen 05.12.2019 St. Gallen, Switzerland Zinkernagel Annelies;
Infetkiologische Fortbildungsreihe, DZIF - translational Seminar Talk given at a conference Chronisch rezidivierende Staphylokokken Infektionen 02.12.2019 Köln, Germany Zinkernagel Annelies;
R&D-Day Talk given at a conference Clinical perspective of chronic - recuring staphylococcal infections 24.10.2019 Karolinska, Russia Zinkernagel Annelies;
IMM Seminar series Individual talk Combination of high virulence and antibiotic persistence in a S. aureus strain resulting in treatment failure 26.09.2019 Zürich, Switzerland Huemer Markus;
14. Luzerner Wundtag - Knacknüsse und neue Therapieansätze in der Wundbehandlung Talk given at a conference Neue Erkenntnisse in der Infetkiolige im Hinblick auf Wundbehandlung 17.09.2019 Luzern, Switzerland Zinkernagel Annelies;
ADA FDI 2019 World Dental Congress San Francisco - 5111 Antibiotics from a Global Point of View - Significance in Dental Medicine Talk given at a conference Antimicrobial resistance and tolerance resulting in treatment failure of infections 05.09.2019 San Francisco, United States of America Zinkernagel Annelies;
GRS/GRC 2019 Staphylococcal Diseases Poster Combination of high virulence and antibiotic persistence in a Staphylococcus aureus strain resulting in treatment failure 03.09.2019 Barcelona, Spain Huemer Markus;
Staphylococcal Diseases - August 2019, Gordon Research Converence Talk given at a conference Clinical perspective of chronic - recuring staphylococcal infections 08.08.2019 Castelldefels, Spain Zinkernagel Annelies;
ESCMID Summer School 2019 Talk given at a conference Complicated soft tissue infections 30.06.2019 Liverpool, Great Britain and Northern Ireland Zinkernagel Annelies;
2019 eCM Orthopedic Infection Talk given at a conference Clinical perspective of chronic - recuring staphylococcal infections 28.06.2019 Davos, Switzerland Zinkernagel Annelies;
Ziischtigs-Fortbildung der Klinik PPK am Zahnmedizinischen Zentrum der Uni Zürich Individual talk Endokarditis und Prophylaxe 21.05.2019 Zürich, Switzerland Zinkernagel Annelies;
Evolutionary bilogy meets the antibiotic crisis, MPI for evolutionary biology Plön Talk given at a conference Clinical perspective of chronic - recuring staphylococcal infections 08.05.2019 Plön, Amsterdam, Netherlands Zinkernagel Annelies;
DGIM 2019 - Komorbidität oder Multimorbidität Talk given at a conference Infektionen bei intravasalen Fremdkörpern 05.05.2019 Wiesbaden, Germany Zinkernagel Annelies;
ECCMID Amsterdam 2019 Talk given at a conference Do we have convincing prclinical data on monoversus combination therapy 14.04.2019 Amsterdam, Netherlands Zinkernagel Annelies;
Day of Clinical research USZ Talk given at a conference Combination of high virulence and antibiotic persistence in a S. aureus strain resulting in treatment failure 11.04.2019 Zürich, Switzerland Huemer Markus;
CABMM Scientific Seminar Talk given at a conference Chronic persistent bacterial infections in clinics 22.03.2019 Zürich, Switzerland Zinkernagel Annelies;
Turkish Clinical Microbiology and Infectious Diseases Congress - KLIMIK 2019 Talk given at a conference Pathogenesis of Gram positive Bacterial Infections - Optimizing Treatment 16.03.2019 Antalya, Turkey Zinkernagel Annelies;
Club de Pathologie Individual talk In-host evolution of Staphylococcus epidermidis in a pacemaker-associated endocarditis resulting in increased antibiotic tolerance 06.02.2019 Bern, Switzerland Häffner Nicola;
VZI-Tagung (Verienigung Allgemeiner Spezialisierter Internistinnen und Intersnisten Zürich) Talk given at a conference Update Infektiologie 31.01.2019 Zürich, Switzerland Zinkernagel Annelies;
13th MIM Introductory Course 2019 Talk given at a conference Clinical perspective of chronic - recuring staphylococcal infections 18.01.2019 Zürich, Switzerland Zinkernagel Annelies;
Infektionen der Lunge - Eine Fortbildung für Lungeninterssierte Lungenzentrum St. Gallen Talk given at a conference Immunologische Abwehrmechanismen und Pathogenitätsfaktoren - Angriffsstrategien 29.11.2018 St. Gallen, Switzerland Zinkernagel Annelies;
Jahrestagung 2018 SSI/SSHH/SSTTMP/SSTT Poster Group A Streptococcal DNase Sda1 impairs plasmacytoid dendritic cells type I interferon response 13.09.2018 Interlaken, Switzerland Keller Nadia;
ESCMID Summer School July 2018 Talk given at a conference Clinical perspective of chronic - recuring staphylococcal infections 23.07.2018 Paris, France Zinkernagel Annelies;
BUSS Summer School Talk given at a conference Bacteria in clinics 18.07.2018 Wolfsberg, Germany Zinkernagel Annelies;
Bacterial Persistence and Antimicrobial Therapy Poster Prolonged lag time results in small colony variants and reflects a sub-population of persisters in vivo 10.06.2018 Ascona, Switzerland Huemer Markus;
EMBO Workshop - Bacterial Persistence and Antimicrobial Therapy Talk given at a conference Clinical perspective of chronic - recuring staphylococcal infections 10.06.2018 Ascona, Switzerland Zinkernagel Annelies;
8th CABMM Spring Seminar Talk given at a conference Presistent Staphylococcus aureus infections - clinical perspective 31.05.2018 Zürich, Switzerland Zinkernagel Annelies;
Molecular and clinical aspects of infection, inflammation and immunity Talk given at a conference A translational perspective of Gram positive bacterial infections 30.05.2018 Tromso, Norway Zinkernagel Annelies;
ECCMID Talk given at a conference Streptocoocal DNase Sda1 interferes with plasmacytoid dendritic cells recruitment and interferon response 23.04.2018 Madrid, Spain Keller Nadia;
ECCMID Madrid 2018 Talk given at a conference Antibiotics and beyond for trating invsive GAS infections 21.04.2018 Madrid, Spain Zinkernagel Annelies;
ECCMID Talk given at a conference In-patient evolution of Staphylococcus epidermidis in a pacemaker-associated endocarditis 21.04.2018 Madrid, Spain Haunreiter Vanina;
Day of clinical Research USZ Poster Prolonged lag time results in small colony variants and reflects a sub-population of persisters in vivo 05.04.2018 Zürich, Switzerland Huemer Markus;
Day of Clinical Research USZ Poster In vivo evolution of Staphylococcus epidermidis in a patient with pacemaker-associated endocarditis 05.04.2018 Zürich, Switzerland Haunreiter Vanina;
Day of Clinical Research USZ Poster Streptococcal Dnase Interferes with Migration and Type I IFN secretion of Plasmacytoid Dendritic Cell 05.04.2018 Zürich, Switzerland Keller Nadia;
Club de Pathologie Individual talk Plasmacytoid Dendritic Cells and Interferon Support Clearance of Group A Streptococcus in Necrotizing Fasciitis 08.02.2018 Bern, Switzerland Keller Nadia;
Kolloquiumsreihe "Molekulare Grundlagen des Lebens" Talk given at a conference Disarming S. pyogenes and S. aureus to treat infections - know your ennemy 15.01.2018 Greifswald, Germany Zinkernagel Annelies;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Die Ärztin, die versteckte Keime bekämpft Tages-Anzeiger German-speaking Switzerland 2019
Media relations: print media, online media Schlafende Bakterien entwischen Antibiotika www.horizonte-magazin.ch German-speaking Switzerland Italian-speaking Switzerland Rhaeto-Romanic Switzerland Western Switzerland 2019

Awards

Title Year
FEMS Meeting Attendance Grant for GRC 2019
Hartmann Müller Travel Grant für GRC 2019

Associated projects

Number Title Start Funding scheme
117303 Exploring bacterial interactions with host phagocytes to identify novel approaches to infectious disease therapy 01.07.2007 SFGBM Fellowships for advanced researchers
184918 Personalized Medicine in cardiovascular infections 01.04.2019 Project funding (Div. I-III)
204343 Tackling difficult-to-treat Staphylococcus aureus infections 01.12.2021 Project funding (Div. I-III)
146295 Circumvention of Host Innate Immune Defenses by Bacterial Nucleases 01.07.2013 Project funding (Div. I-III)
170811 Enhanced Resolution Confocal Laser Scanning Microscope 01.10.2017 R'EQUIP
108365 Boosting the Innate Immune Capacity of Phagocytes as Adjunctive Therapy for Complicated Bacterial Infections 01.07.2005 Fellowships for prospective researchers
130748 Importance of the M1 Protein Structure for Virulence of Group A Streptococcus 01.11.2010 Project funding (Div. I-III)
170799 High content confocal imaging of cellular phenotypes in health and disease 01.12.2016 R'EQUIP

Abstract

Background: Recurrent or chronic infections are an unsolved clinical problem despite the availability of antibiotics to which the bacteria are susceptible. Bacteria isolated from recurrent or chronic infections are in a dormant, non-growing state, tolerate antibiotic challenges and are capable of resuming growth. These bacteria are called persisters. In the clinical context, persistence is defined as ongoing bacterial infection despite treatment with adequate antibiotics i.e. at sufficiently high concentrations with an antibiotic to which the bacterium is susceptible. Persisters are not actively growing and therefore protected from antibiotics which always target processes in growing cells such as cell wall synthesis, DNA replication or protein synthesis. Due to their hibernating state, characterization of persisters is difficult since all cultivation techniques require the bacterium to alter its phenotype and to switch back to an antibiotic-susceptible phenotype. Bacteria isolated from chronic infections in the clinical microbiology laboratory may appear as small colony variants (SCVs) upon cultivation on solid media. As the name suggests, SCVs form atypically small colonies. SCVs are formed by various human pathogens including Staphylococcus aureus. S. aureus is one of the most frequently isolated bacterium responsible for clinically relevant hospital and community acquired infections and is often difficult to treat due to antibiotic resistances. However, chronic or relapsing infections due to antibiotic susceptible S. aureus are an even greater concern worldwide causing high morbidity and mortality and necessitate prolonged antibiotic treatment. Hypothesis: Since persisting bacteria are in a dormant non-growing state we hypothesize that a lag phase in their growth could lead to a smaller colony size compared to colonies formed by non-dormant bacteria. We propose that a part of the viable but dormant non-growing bacteria resume growth after plating on nutrient-rich pH-neutral agar plates with a lag time explaining the various colony sizes on agar plates. We speculate that the presence of SCVs in the diagnostic microbiological laboratory mirrors the presence of bacterial persisters in the patient which arise due to specific stressors encountered in the host. Eliminating a specific stressor will reduce the formation of S. aureus persisters/SCVs.Approach: We propose to study the formation of SCVs and persisters and whether they are the same or at least variants of the same phenomenon. In addition, we will investigate the relation between bacterial persisters/SCVs and the clinical problem of recurrent infections as observed for example in abscesses in mouse and man using S. aureus as a model organism. We aim to define and characterize persisting S. aureus by assessing growth kinetics using an automated agar plate imaging system as well as single cell time-lapse microscopy. In addition, the classical biphasic antibiotic persister assay will be carried out, in which an initial rapid killing of the bulk population and a plateau where only the persister subpopulation remains alive, is observed. We will assess genetic and environmental factors influencing clinical S. aureus persister/SCVs formation using clinical isolates from acute and chronic infections. Relevance: Persisters are dormant bacteria capable of re-growth and likely allowing chronic and relapsing, clinically significant infections. Such infections cause a substantial burden of disease despite current state-of-the-art antibiotic therapy and are a major cause of antibiotic treatment failure. A better understanding of this phenomenon will significantly impact patient’s health. Data generated in this project will provide new insights into host/pathogen interactions. We will dissect how persisters and SCVs relate. Better characterization and identification of bacterial persisters/SCVs could in a next step allow early adaption of antibiotic treatment regimes. Thus, this research proposal has the potential to impact directly clinical research by identifying new antibiotic targets and/or facilitating new antimicrobial therapies with increased efficacy which will help to reduce antibiotic exposure and treatment-associated costs.
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