Jan Michiels Lab

Research focus

Antibiotics have revolutionised medical practice by successfully combatting life-threatening infectious diseases. However, many bacterial pathogens have become resistant to different classes of antibiotics making treatment in many cases problematic. In addition to the problem of genetic resistance, antibiotics are also unable to completely sterilize genetically susceptible bacterial populations because of the presence of a small fraction of non-growing, transiently antibiotic-tolerant ‘persister’ cells. Persisters are an important but neglected clinical concern as they underlie antimicrobial therapy failure and recurrence of chronic infections. This is especially relevant when persisters cannot be cleared by the immune system because of restricted access (e.g. in biofilms or intracellular infections), or an impaired immune response. 

The primary focus of the Michiels lab is to uncover the basic molecular principles of bacterial persistence and how bacteria enter or exit this state. Understanding the underlying molecular mechanisms may help to develop new therapeutic approaches to combat pathogenic bacteria. From an evolutionary point of view, we explore how bacterial populations adapt persistence characteristics by genetic mutations or epigenetic modifications during fluctuating antibiotic regimens. In this context, we also examine the link between persistence and the evolution of genetic antibiotic resistance. We focus on the model bacterium Escherichia coli and several pathogenic species including the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.).

We use genetic approaches combined with ‘omics’ analyses (genomics, transcriptomics, proteomics) and advanced microscopy, as well as bioinformatics examinations and mathematical modelling. Research is performed both at population and at single-cell levels as well as during interaction with the eukaryotic host (cellular and animal models).


​®Liselot Dewachter

 
Additional research topics

Over the past years, we have set up successful antimicrobial discovery pipelines (>40.000 compounds screened in different set-ups) and performed structure-activity, mode-of-action and toxicity analyses of multiple target compounds. For this, we have used a variety of bacterial pathogens including the ESKAPE pathogens, Streptococcus mutans and Porphyromonas gingivalis which are involved in periodontal diseases. We have in-house cellular assays, and are actively collaborating with several groups for compound testing in small animal models for urinary tract infections, subcutaneous biofilm infections and lung infections.
We are also studying the complex genetics of ethanol tolerance in E. coli. Using experimental evolution, we demonstrated an unexpected flexibility in cellular mutation rates as a response to changes in ethanol levels. Specifically, as the ethanol stress increased, mutator alleles accumulated in the adaptive lineages. With stabilization of the ethanol concentration, these same lineages acquired compensating anti-mutator alleles. These findings show how organisms balance robustness and evolvability and help explain the prevalence of hypermutation in various settings. Moreover, we have been able to drastically increase ethanol tolerance in E. coli and identify adaptive pathways using network-based approaches. These findings can provide a general framework to improve tolerance to various value-added chemicals in different bacterial species.
We also seek to improve survival of nitrogen-fixing rhizobia using advanced genetic techniques in a diverse collection of natural isolates. The major aim here is to improve survival of dormant Rhizobium in legume seed coatings by enhancing stress tolerance.

​​​

Publications

Formation, physiology, ecology, evolution and clinical importance of bacterial persistersVan den Bergh B, Fauvart M, Michiels JFEMS MICROBIOLOGY REVIEWS, 41, 219-251, 2017
Network-based identification of adaptive pathways in evolved ethanol-tolerant bacterial populationsSwings T, Weytjens B, Schalck T, Bonte C, Verstraeten N, Michiels J, Marchal KMOLECULAR BIOLOGY AND EVOLUTION, e-pub, e-pub, 2017
Adaptive tuning of mutation rates allows fast response to lethal stress in Escherichia coliSwings T, Van Den Bergh B, Wuyts S, Oeyen E, Voordeckers K, Verstrepen K, Fauvart M, Verstraeten N, Michiels JeLife, 6, e22939, 2017
Frequency of antibiotic application drives rapid evolutionary adaptation of Escherichia coli persistenceVan Den Bergh B Michiels E* Wenseleers T* Windels E Boer P Kestemont D De Meester L Verstrepen K Verstraeten N Fauvart M* Michiels J*NATURE MICROBIOLOGY, 1, 16020, 2016* These authors contributed equally
Obg and Membrane Depolarization Are Part of a Microbial Bet-Hedging Strategy that Leads to Antibiotic ToleranceVerstraeten N* Knapen W* Kint C Liebens V Van Den Bergh B Dewachter L Michiels J Fu Q David C Fierro A Marchal K Beirlant J Versées W Hofkens J Jansen M Fauvart M* Michiels J*MOLECULAR CELL, 59, 9-21, 2015* These authors contributed equally

Job openings

Jan Michiels

Jan Michiels

Research area(s)

Model organism(s)

Bio

​Ph​D: KU Leuven, Leuven, Belgium, 1989-93
Postdoc: KU Leuven, Leuven, Belgium, 1993-01
Group leader: KU Leuven, Leuven, Belgium since 2001
Director of the Centre of Microbial & Plant Genetics, KU Leuven, Belgium since 2015
​Francqui Research Professor, KU Leuven, Belgium 2017-21
VIB Group leader as of October 2017

Contact Info

VIB-KU Leuven Center for MicrobiologyKasteelpark Arenberg 31 bus 2438 3001 LEUVEN