Molecular Microbiology has three main research themes
1 – Protein trafficking in Gram-negative and Gram-positive bacteria
In this theme, we focus on protein trafficking in bacteria. In particular, we examine insertion, folding and assembly of membrane proteins in both the cytoplasmic and outer membrane of the bacterial cell envelope. In addition, we study trans-envelope transport via the type V secretion system, a route that is taken by many virulence factors of Gram-negative pathogenic bacteria. Our fundamental research is aimed at elucidating mechanistic details at the molecular level, but we also have a keen eye for applicable spin-offs, which includes the development of approaches to secrete recombinant proteins in biotech production processes.
- Role of Bam complex in cell envelope biogenesis and protein secretion [Luirink, van Ulsen, Koningstein]
- Improving protein secretion in Bacillus subtilis [Luirink, van Ulsen, Kes]
- Induction of vesicle formation in Gram-negative bacteria [Luirink, van Ulsen, Koningstein]
- Development of bacterial-based vaccines against Chlamydia [Luirink, van Ulsen, Huynh], pneumococcal disease [Luirink, de Jonge] and cancer [van Kooyk, Luirink, van Brekel]; in collaboration with embedded spin-off company Abera Bioscience (https://aberabio.com)
2 – Cell envelope processes in pathogenic mycobacteria
Mycobacteria represent a group of bacteria that include many important pathogens such as Mycobacterium tuberculosis, the causative agent of tuberculosis, and our model organism, the fish pathogen Mycobacterium marinum. These bacteria are very different from other bacteria in several aspects, particularly regarding the built-up of their exceptionally lipid-rich and impermeable cell envelope. In this research theme, we use state-of-the-art genetic, molecular and biochemical tools to understand the mechanism of transport of proteins, nutrients and DNA across this specific cell envelope. In addition, we study the roles of mycobacterial type VII secretion systems and the proteins these systems export in mycobacterial virulence using a range of infection models.
- Substrate recognition by the mycobacterial type VII secretion systems [Houben, Bitter, Damen, Keizer]
- Substrate transport through the type VII secretion membrane channel [Houben, Bitter, Ding, Keizer]
- Elucidation of mycobacterial outer membrane proteins [Bitter, Speer, Houben, Izquierdo Lafuente, Keizer]
- Mechanism of mycobacterial conjugation [Bitter, Ummels, Coenraads]
- Roles of lipoproteins in mycobacterial infection [Bitter, Nejentsev, Lissner]
3 – Discovery of antibiotics targeting the bacterial cell envelope or bacterial metabolism
To combat Gram-negative pathogens we develop innovative strategies for the discovery and development of new antibiotics that target the outer membrane Bam protein complex. Specific to Gram-negative bacteria, the Bam complex plays an essential role in the biogenesis of the outer membrane and the secretion of virulence factors. To combat Mycobacterium tuberculosis and related mycobacteria, we elucidate the function of protein complexes in (energy) metabolism and characterize novel antibiotics that interfere with the function this central pathway. Targeting energy metabolism has emerged as a highly successful strategy to tackle this prominent pathogen. In addition, we use our zebrafish embryo infection model to screen directly for compounds that work in vivo.
- Development of cell envelope biogenesis inhibitors [Luirink, van Ulsen, Koningstein]
- Cell division: targeting the FtsQ-FtsB membrane complex [Grossmann, Luirink, Paulussen]
- Using the zebrafish infection model to identify drugs that are active in vivo [van Ulsen, Bitter, Speer, Verboom, Schouten, Habjan]
- Functional investigation of a bacterial defense factor [Bald, Goojani, Besharati]
- Innovative approaches to identify persisters in mycobacterial populations [Bald, Bruggeman, Chauhan]
- Characterization of novel drugs targeting mycobacterial energy metabolism [Bald, Goojani, Chauhan]