Antibiotic Lead Optimization

Projektbeschreibung

Antibiotikaentwicklung zur Bekämpfung multiresistenter Infektionen

Die Bedrohung durch antimikrobielle Resistenzen stellt heute eine der drängendsten Herausforderungen für die globale Gesundheit dar, da sich multiresistente Krankheitserreger rasch ausbreiten. Es werden dringend neue Antibiotika benötigt, um Infektionen zu bekämpfen, die mit den konventionellen Medikamenten nicht mehr behandelbar sind. Die heute üblichen Behandlungen werden immer unwirksamer, was erhöhte Sterblichkeit und Komplikationen nach sich zieht. Die Suche nach innovativen Zielmolekülen für Antibiotika ist entscheidend, um diese Krise zu überwinden. In diesem Zusammenhang ist die Arbeit des ERC-finanzierten Projekts AnLeadOp darauf ausgerichtet, eine vielversprechende neue Klasse von Antibiotika zu optimieren, die auf die bakterielle DNA-Klammer (DnaN) abzielt, wobei dieser Durchbruch in früheren Forschungsarbeiten erarbeitet wurde. Anhand der Bewertung ihrer antibakteriellen Eigenschaften und ihrer In-vivo-Wirksamkeit werden im Rahmen des Projekts präklinische Leitkandidaten zur Bekämpfung bakterieller multiresistenter Infektionen entwickelt.

Ziel

The bacterial sliding clamp (DnaN) is an innovative target for the development of novel antibiotics, which are urgently needed to overcome the alarming antimicrobial resistance crisis. In the previous ERC starting grant (NovAnI), we discovered a novel DnaN inhibitor (WAM-N17) with promising broad-spectrum antibacterial activity including multidrug-resistant (MDR) pathogens. In this PoC project, we will optimize the antibacterial potency and spectrum and characterize the in vivo pharmacokinetic (PK) and pharmacodynamic (PD) properties of the WAM-N17 class so as to develop preclinical lead candidates for the treatment of bacterial infections, especially those caused by MDR germs. To achieve this goal, we will pursue three main activities. (i) Design and synthesis of 25–30 compounds (in two rounds) with modifications focusing on improving the anti-Gram-negative activity as well as target identification through chemical probes to further validate DnaN and identify other potential targets in bacteria. (ii) Evaluation of antibacterial activity, target binding/inhibition, and in vitro ADME-T (absorption, distribution, metabolism, excretion, toxicity) characterization for all new compounds. The frontrunners will be profiled for antibacterial activity against an extended panel of Gram-negative and MDR clinical isolates and subjected to mode of action (MoA) and target-identification studies. The most promising ten compounds will be submitted for in vivo PK studies and the best two lead candidates will be tested in a proof-of-concept in vivo efficacy study using relevant infection mouse models. (iii) Ultimately, we will file a patent to secure our intellectual property rights and continue to move this class of compounds forward into preclinical and then clinical studies in collaboration with a pharmaceutical industry partner. The knowledge that will be gained from this PoC project is essential to develop an urgently needed new antibiotic with an unprecedented mode of action.