Dr Kai Hilpert is developing antimicrobial peptides into drugs against multidrug-resistant bacteria.
Antibiotics are an important pillar on which many branches of modern medicine rest. Resistance and multi-drug resistance undermine this pillar and strategies are needed to develop new treatments for bacterial infections. In this ambitious project we are addressing the development of new antimicrobial drugs with novel modes of action.
AMPs
Research in the last two decades demonstrates that antimicrobial peptides (AMPs) can be divided into many different classes and have many different modes of action. AMPs also have desirable features of being fast acting, a low tendency to cause resistance and the ability to kill multi-drug resistant gram-positive and gram-negative bacteria. However, many AMPs also possess undesirable features, such as haemolytic and cytotoxic activity, low stability in serum and low oral bioavailability.
We invested a lot of time and energy to understand these features and overcome them. We are the first research group in the world to predict and rank whole classes of peptides, not only for their antimicrobial activity but also for their haemolytic/cytotoxic activity. We can design and optimise peptides in silico with the best therapeutic potential.
Therapeutic potential
In collaboration with Dr Chris Creevey (Queens University Belfast), we are screening whole genomes of microbes, plants and animals for antimicrobial peptides with high therapeutic potential. With this large pool of peptides comes the question of which ones are worth to pursue. We believe that candidate peptides need to have a different mode of action from each other but also a different mode of action from conventional antibiotics to avoid the fast development of cross-resistance that would make a new drug unusable.
Novel methodology
We have developed and validated a novel method for the high-throughput (5 sec per sample) investigation of mode-of-action (MOA) of AMPs based on small angle x-ray scattering (SAXS; 1, 2). We have used this method to group peptides according to different modes of action (unpublished results). Based on our data to date we have selected several peptide leads with promising antibacterial activity, low toxicity and different modes-of-action to progress through an evaluation cascade towards selection of one or more drug candidates.
Furthermore, we have already discovered a method to improve the stability of AMPs in serum dramatically that will speed up the development of peptides for systemic use. This ability to predict peptide activity and toxicity, together with rapid MOA understanding and stability in serum has never been achieved before and brings us into a position where we can finally unlock the promise of this valuable class of potential new antibiotics.
Publications
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von Gundlach at al. J Appl Crystallogr. 2016;49(Pt 6):2210-2216
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von Gundlach et al. Biochim Biophys Acta. 2016;1858(5):918-25
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Knappe at al. Antimicrob Agents Chemother. 2010, 54(9): 4003–4005.