Oscar Kuipers is a member of the European Academy of Microbiology (EAM). The EAM is a leadership group of around 130 eminent microbiology experts who came together in 2009 to amplify the impact of microbiology and microbiologists in Europe.
Oscar Kuipers is a full professor in Molecular Genetics and has headed the Molecular Genetics research group at the University of Groningen since 1999. Trained in molecular biology and biochemistry, he moved towards molecular genetics and synthetic biology after completing his PhD. We caught up with Prof. Oscar Kuipers to find out more about him and his research.
Professor Kuipers’ research focuses on three main areas:
- New antimicrobials: Prof. Kuipers is an expert on the biosynthesis, function, engineering, and regulation of modified antimicrobial peptides produced by bacteria (known as ‘lantibiotics’). Major discoveries and developments in this area include the unravelling of the biosynthesis route of the paradigm lantibiotic nisin and the first lantibiotic protein engineering paper, which demonstrated that it is possible to make variant molecules with altered activities (JBC 1992). This discovery opened up a wide range of possibilities to create novel antimicrobials with an altered spectrum and improved antimicrobial activity.
- Population heterogeneity and bistability at the single-cell level: From 2003 onwards, Prof. Kuipers has carried out pioneering research into single-cell biology, unravelling the mechanisms leading to phenotypic heterogeneity in bacterial populations. His key realization was that differentiation and heterogeneity in bacterial cultures, hitherto commonly treated as homogeneous, is omnipresent and bears important implications for bacterial behaviour. These insights into differentiation and heterogeneity are now being used to develop novel strategies to fight unwanted bacteria (in the interest of human health and in industrial settings), and to study persisters and heteroresisters.
- Bacterial gene regulation and genomics: Since 2000, Prof. Kuipers has used transcriptomics and bioinformatics to study gene regulation and gene regulatory networks in Gram-positive bacteria. His group has developed more than 20 frequently used bioinformatics tools, including BAGEL, a web-based bactericin genome-mining tool. His work has contributed to a wide array of research topics, including competence development, sporulation, germination, biofilm formation, metal-ion stress, carbohydrate utilization, N-metabolism and general stress response, and recently started focusing on cells in microbial populations that are highly resistant to antimicrobials (persisters and heteroresisters). Currently, his group is heavily focused on developing novel antimicrobials, using lantibiotics as an inspirational template. Utilizing the modular structure of lantibiotics, a strategy employing synthetic biology principles has been developed, leading to the design of hundreds of thousands of new-to-Nature molecules in an in vivo plug-and-play system. In collaboration with Professor Sven Panke (ETH Basel), large libraries have been screened and over 20 completely novel compounds have been identified that have high activity against selected pathogens (VRE, MRSA). Several technological innovations that were achieved throughout this work include the development of systems for inducible gene expression in Gram-positive bacteria that are now used in more than 100 labs worldwide, and the development of plug-and-play expression systems for combinatorial lantibiotic production.
Could you tell us about your research interests?
“We develop novel antibiotics based on modified peptide templates using synthetic biology approaches. We do this by combining the biosynthetic machinery of various modified peptide families such as lantibiotics, microcins, lassopeptides, and sactipeptides. Our work is also concerned with heterogeneity in clonal populations studied by time lapse microscopy, microfluidics and flow-cytometry.”
What has been the most unusual or surprising finding in this line of research?
“There have been a number of surprising findings in this line of research. Several of the most notable include:
- Autoinduction of lantibiotic biosynthesis
- Promiscuity of lantibiotics enzymes, so you can exploit them to make novel modified peptides
- Identification of lipid II as a receptor for lantibiotics
- Molecular basis of bethedging elucidated.”
What has been the most challenging aspect of this project?
“Several key challenges have included:
- Obtaining ring-shuffled molecules with good activity
- Improving the homogeneity and yield of produced variants with high antimicrobial activity
- Obtaining molecules to which resistance development is not readily occurring.”
What aspect of this project have you most enjoyed?
“I’ve most enjoyed engineering combinations of modification machineries in one cell. This is a great challenge. We’re aiming to obtain new antibiotics that make it to clinic. I hope that our new-to-nature molecules in the natural product range will have many possible applications.”
How many people are in your research group?
“I head the group of Molecular Genetics with 55 people. 34 of these are PhD students, postdocs, and technicians, who I supervise directly. The others are supervised by my colleagues, Professor Jan Kok and Professor Jan Willem Veening.”
What is the range of academic levels represented among your group members?
“We have about 55 scientists in our group, representing 16 nationalities (50% PhD students, 25% postdocs, 15% Master students, 5% technicians, 5% staff members). We like to work in smaller teams and frequently collaborate with each other through monthly team meetings as well as more informal meetings and conversations. I always encourage collaboration.”
What is the favorite aspect of your research?
“I most enjoy the discussions with the PhD students and postdocs. The excitement when experiments show something completely novel and, of course, the final understanding of a mechanism are also highlights.”
What has been your most memorable moment in a lab (or in the field) thus far in your career?
“The final understanding of autoinduction by nisin of its own operon was a real Aha-Erlebnis. The engineering of active phospholipase mutants and their refolding from E.coli inclusion bodies was a real breakthrough too. The engineering of completely novel modified peptides which show great activity was an exciting finding as well.”