Assault, Siege, Trojan Horses or Gentle Disarmament: Molecular Strategies to Fight Bacterial Infections
Sprecher: Mark Brönstrup (HZI/Leibniz-Universität Hannover)
Gastgeber: Samuel Wagner
Datum & Uhrzeit: 16.05.2024 | 12:30 – 14:00 Uhr
Ort: Hörsaal 3M07, GUZ
Öffentliche Veranstaltung. Keine Anmeldung erforderlich.
Abstract:
Multidrug resistant bacterial pathogens have become a major health concern. We have investigated various chemical strategies for selective targeting, breaking resistance or ameliorating bacterial infections.
A broad spectrum of gram-positive and gram-negative pathogens is addressed by cystobactamids, oligo-arylamids originally isolated from Cystobacter sp. Our efforts to optimize the antibiotic properties of the cystobactamids by medicinal chemistry to resistance-breaking, in vivo active leads will be presented.[1] Beyond a classic ‘assault’ of bacteria with such antibiotics, the conjugation of natural products to targeting functions has been beneficial to improve their drug properties. In the so-called Trojan Horse Strategy, antibiotics are conjugated to siderophores to hijack the bacterial iron transport system, and thereby enhance the intracellular accumulation of drugs. We present novel artificial siderophores, characterize their transport and resistance mechanisms, and their ability to deliver large cargo for the diagnosis or the treatment of infections.[2,3] An infection-triggered release of antibiotic conjugates was realized in the alternative siege concept, using the lipopeptide colistin as the antibiotic effector.[4] Finally, our latest work on developing first-in-class, in vivo active hemolysin-alpha inhibitors that disarm the pathogen S. aureus will be shown.
1) G. Testolin et al., Chem. Sci. 2020, 11, 1316 – 1334. 2) C. Peukert et al., Angew. Chem. Int. Ed. 2022, e202201423. 3) C. Peukert et al. Chem. Sci. 2023, 14, 5490 - 5502. 4) W. Tegge et al., Angew. Chem. Int. Ed. 2021, 60, 17989-17997.