Pan European Networks - Horizon 2020 - page 191

C
hronic or persistent microbial infections are a worldwide
problem and constitute a major cause of morbidity and
mortality for patients and a burden for healthcare
systems. These infections are caused by pathogens that evade the
host immune system and persist for long periods of time in the
host, creating a reservoir of bacteria. Persistent infections may
lead to chronic symptoms or remain clinically asymptomatic while
reactivating at a later time. Classic examples include tuberculosis
caused by
Mycobacterium tuberculosis
infections, chronic cystitis
resulting from urinary tract infections by uropathogenic
Escherichia coli,
and chronic lung infections caused by
Pseudomonas aeruginosa
in patients suffering from cystic
fibrosis. In addition, a major source of hospital-acquired
persistent infections is infected foreign bodies such as central
venous catheters and prosthetic implants on which bacteria often
build recalcitrant biofilms. Biofilms are surface-associated
communities of micro-organisms embedded in exopolymers,
providing a protected niche.
Antibiotic-tolerant bacteria in chronic infections
Chronic microbial infections are notoriously difficult to treat with
antibiotics, although the bacteria are often drug-sensitive. It has
become clear in recent years that one of the main causes is a
distinct physiological state of the bacteria. Specialised cells,
termed persisters, are the main explanation of biofilm tolerance
and the major culprit for treatment failure of biofilm-associated
infections (Fauvart
et al. J. Med. Microbiol.,
2011). Persisters are
dormant cells that are transiently insensitive to high doses of
antibiotics (Kint
et al. Trends Microbiol.,
2012). When antibiotic
concentrations decline, persister cells resuscitate and repopulate
the biofilm, resulting in a relapse of infection. Understanding the
molecular mechanisms that underlie the formation of persisters
and their exit from dormancy will help us to develop novel
therapeutic approaches and adapt existing treatment regimens to
combat chronic infections.
Approaches towards understanding and combatting
antibiotic-tolerant bacteria
The Symbiotic and Pathogenic Interactions Group at the Centre of
Microbial and Plant Genetics, University of Leuven, investigates
the physiology and genetic basis of persisters in different bacteria,
including important human pathogens such as uropathogenic
E.
coli, P. aeruginosa, Salmonella
Typhimurium and
Staphylococcus
aureus.
Our aim is to understand from a fundamental point of
view the mechanistic basis of persister formation as well as the
evolutionary dynamics of persistent populations in the presence
of antibiotic pressure. Ultimately, our goal is to develop new
therapeutic options for chronic infections.
To achieve this goal, we have developed both potent genetic
screens and cutting-edge single-cell visualisation tools to study
model bacterial strains and clinical isolates. Eukaryotic cellular
systems as well as animal models are used to study the relevance
of our findings
in vivo.
Our results demonstrate that specific
stress-resistance pathways and mechanisms controlling the
cellular energy status determine the formation of antibiotic-
tolerant cells and their exit from this status. Recently, in a search
for new therapeutics to be used in combination with existing
antibiotics, we have identified different classes of small molecules
that rapidly kill surviving antibiotic-tolerant persister cells both
in
vitro
and in cellular systems.
We collaborate with many international and national groups of
universities, research centres and hospitals. For example, in the
on-going EU Seventh Framework Programme HEALTH project
COATIM, in collaboration with Professor B Cammue and Dr K
Thevissen (University of Leuven), we are developing implant
coatings containing novel potent molecules directed against
bacterial and fungal biofilms.
Jan Michiels, PhD
Professor of Molecular Microbiology
Symbiotic and Pathogenic Interactions Group
Centre of Microbial and Plant Genetics
University of Leuven
te l :
+32 16321631
The group of Professor Jan Michiels at the University of Leuven investigates the
molecular mechanisms underlying bacterial antibiotic tolerance or persistence in
chronic infections
Antibiotic tolerance
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I S S U E S I X
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