Research Highlights

Prof. dr. Oscar Kuipers

Antibiotic resistance in human pathogens is on the rise and and new approved antibiotics are needed to combat resistant bacteria. The Kuipers group investigates the class of ribosome-synthesized peptides, called lantibiotics. Lantibiotics are potent antimicrobial peptides that undergo extensive posttranslational modifications. In an attempt to improve the spectrum of lantibiotics against Gram-negative microorganisms, we designed different fusions of peptides to parts of nisin that retain the lipid II binding activitya-c. Thereby, we combine the outer membrane traversing activity of peptides with the lipid II binding activity of nisin. Several multivalent nisin derivatives were produced by Lactococcus lactis, purified and tested against different bacteria, and some of them showed an increased activity against Escherichia colic. These results present a promising strategy for the rational design and production of novel multivalent lantibiotics targeting Gram-negative bacteria. Moreover, we have used several other approaches to develop novel antimicrobials or to get insight in resistance development; for instance, i) a synthetic biology approach to efficiently use the large amount of sequenced genomes (>4,000) as a resource for novel lantibioticsd-g, ii) use of additional heterologously expressed post-translational modification enzymes to hypermodify lantibioticsb,f,h, iii) design and production of novel lantibiotics by ring module- and hinge-variation or introduction of non-canonical amino acidsj,k, iv) Mimicking NRPs by ribosomal synthesis and extensive posttranslational modification (this remains the core activity now, and is very successful with several papers in preparation)

Related papers with Oscar Kuipers as (one of the) leading author(s)

aScience (2006); bFEMS Microbiology Reviews (2016); cFrontiers in Cell and Developmental Biology (2016); dNucleic Acids Research (2013); eBMC Genomics (2016); fACS Synthetic Biology (2016); gNature Chemical Biology (2015); hACS Synthetic Biology (2013); iFrontiers in Microbiology (2015); jAmino Acids (2017); kFrontiers in Microbiology (2017); lPNAS USA (2014) and various subsequent papers in ACS Synthetic Biology, Cell Chemical Biology, Nature Communications, Journal of Antimicrobial Agents, FEMS Microbiology Reviews, Natural Product Reports, etc.