Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - SUPRABIOTICS (Supramolecular Protective Groups Enabling Antibiotics and Bioimaging)

Teaser

The pharmaceutical sector has a huge demand for new active compounds including natural products to fill the drug pipelines and to stop the global decline in novel approved active pharmaceutical ingredients. Therefore, developing new tools to fabricate complex molecular...

Summary

The pharmaceutical sector has a huge demand for new active compounds including natural products to fill the drug pipelines and to stop the global decline in novel approved active pharmaceutical ingredients. Therefore, developing new tools to fabricate complex molecular structures in a fast and reliable way is paramount. This holds especially true for the field of antibiotics. Multidrug resistant (MDR) pathogens evolve at a terrifying rate and confer resistance to all presently available antibacterial treatments, leading the WHO to condemn MDR bacteria as a major threat to human health.
In this ERC Advanced Grant, a new approach to fabricate very complex molecules with minimal synthetic effort is pursued. The technology is based on nucleic acid binders (aptamers), which are evolved to bind a target molecule and block several functional groups within that molecule while allowing other functionalities not in contact with the aptamer to be selectively modified in a single reaction step. Here, we aim to establish this technology as a novel tool that gives access to compounds that would otherwise be too difficult to obtain by multistep synthesis. The resulting compounds will be employed to synthesize novel antibiotics that kill MDR bacteria, to fabricate imaging reagents for infections and to develop probes for RNA imaging.

Work performed

In the course of the project, we have synthesized labelled aminoglycoside antibiotics, which selectively stain gram negative bacteria. The conjugates can be employed to image bacterial infections in vivo by means of fluorescence. Moreover, we have synthesized antibiotics that can be switched by light between two states. In one state they allow to kill resistant bacteria while in the other state they are not active against these pathogens. Finally, we have fabricated probes that rely on antibiotic compounds, which allow the visualization of RNA in living cells.

Final results

Bacteria are classified in gram-positive and gram-negative ones, which is important for antibiotic treatment. They can be classified by staining, however, this procedure is not compatible with live bacteria and an in vivo situation. For the first time, we present a staining reagent that allows staining of gram-negative bacteria and at the same time functions as a bioimaging reagent in vivo.
In the field of photopharmacology, antibiotics have been developed, which allow the activation of antibiotics by light. However, these compounds have never been investigated in the context of resistant bacteria. Here we have fabricated the first photoswitchable aminoglycoside. This drug is able to overcome drug resistance in one state while being inactive against the resistant pathogens in the other state. After activation by light, the compound slowly transforms from the active into the inactive form. With this new class of antibacterials, it is possible to keep evolution of the development of new resistance genes low since the compound intrinsically deactivates itself by an intrinsic mechanism. Finally, we have developed probes that allow the visualization of RNA in living cells. Before, these probes were less selective, moderately entered cells and exhibited low solubility in water. Our new probes overcome these three shortcomings.