Drug Design and Optimization
In order to combat the increasing number of resistant pathogens, the development of new anti-infective drugs is an important goal for pharmaceutical research. Efficient medications with novel modes-of-action to fight infectious diseases are urgently needed. Below, you may read more about the design, identification and optimisation of new drug candidates. This group is located at the Helmholtz Institute for Pharmaceutical research Saarland (HIPS).
In the department “Drug Design and Optimization”, scientists design and optimize compounds that avoid the increasing resistance of pathogens to commonly used antibiotics. To do so, both established and innovative strategies to facilitate hit identification and optimization are applied. The new compounds should interfere with essential processes within the pathogens in order to kill them or to reduce their pathogenicity.
One such important mechanism for bacteria is “quorum sensing” – a cell-to-cell communication system, which employs chemical signals known as autoinducers. Through the use of these signalling molecules, pathogens coordinate population-wide group behaviours such as virulence-factor production or biofilm formation in a cell density-dependent manner, hence, orchestrating and promoting the infection process.
Bacteria build a dense layer, the biofilm, which enables self-protection against an immune response. Additionally, biofilms can suppress the uptake and/or activity of antibiotics resulting in tolerant or even resistant bacteria. The research group focuses on the signalling molecule PQS, which only exists in the human pathogenic bacterium Pseudomonas aeruginosa.
The aim is to develop agents that interfere with PQS signalling for the treatment of severe and life-threatening chronic infections. Individuals with an impaired immune system or disrupted defence barriers, like patients suffering from cystic fibrosis or burn wounds, are at high risk to acquire notoriously difficult to treat infections once they are hospitalised. The intrinsic tolerance of P. aeruginosa toward a broad range of antibiotics combined with an alarming occurrence of multi-drug resistant strains necessitate innovative anti-infective approaches such as the proposed quorum-sensing inhibitor strategy.
Another essential mechanism is the biosynthesis of the universal precursors of the natural product class of isoprenoids. Important pathogens such as Mycobacterium tuberculosis and Plasmodium falciparum use the methyl erythritol phosphate pathway that is distinct from the mevalonate pathway used by humans. As a result, the constituent enzymes are excellent drug targets for the development of novel anti-infectives. By applying a variety of hit-identification strategies, the research group identified various structurally distinct hits that are now being pursued and further optimised.
A third example of an essential process in bacteria is the transcription of their genetic information. The inhibition of such an important function leads to the bacteria’s death. Therefore, we focus on the development of inhibitors blocking the transcription of bacterial genes by inhibiting the RNA polymerase (RNAP), an enzyme that plays an essential role in the survival of bacteria. This enzyme transcribes DNA into RNA, thereby enabling the cell to produce proteins from the genetic information. The targeted bacteria are pathogenic to humans and cause serious diseases. One example is Mycobacterium tuberculosis, the cause of tuberculosis, which leads to two million deaths per year worldwide.
In all projects, the scientists apply a series of established hit-identification strategies, including structure- and fragment-based drug design, classical medicinal chemistry, virtual screening as well as innovative methods such as dynamic combinatorial chemistry and kinetic target-guided synthesis. During the optimization of the new inhibitors of the various drug targets, their mechanism of inhibition is characterised to ensure that the agents are not only highly potent, but that they also enter pathogenic cells to unfold their anti-infective effect.
Scientists in the interdisciplinary research group have diverse backgrounds such as medicinal chemistry, synthetic organic chemistry, pharmacy, pharmacology, biology or biochemistry, resulting in a diverse skill set.
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- Kündigung für Biofilm-WGs – Pharmazeuten des HIPS stören BakteriengemeinschaftenBakterien haben einen ausgeprägten Gemeinschaftssinn und verschanzen sich gerne in schleimigen Biofilmen. Etwa 60 Prozent aller bakteriellen Infektionen lösen inzwischen Biofilme aus. Ein besonders geselliger Keim ist Pseudomonas aeruginosa. Er ist besonders für Mukoviszidose-Patienten gefährlich. Wissenschaftler am Helmholtz-Institut für Pharmazeutische Forschung Saarland suchen nach Wegen, seine Biofilme aufzulösen – damit Medikamente wirken können. Begleiten Sie Anke Steinbach in Ihre Labore...