Next Generation Polymyxin Antibiotics: Optimization and Validation

Projektinformationen

NOVA

ID Finanzhilfevereinbarung: 101082241

DOI

10.3030/101082241

Projekt abgeschlossen

EK-Unterschriftsdatum 18 Oktober 2022

Startdatum 1 November 2022

Enddatum 30 April 2024

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

Keine Daten

EU-Beitrag

€ 150 000,00

Koordiniert durch

UNIVERSITEIT LEIDEN
Netherlands

Periodic Reporting for period 1 - NOVA (Next Generation Polymyxin Antibiotics: Optimization and Validation)

Berichtszeitraum: 2022-11-01 bis 2024-04-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

The primary objective of the NOVA ERC Proof of Concept project was to determine the technical and commercial feasibility of a novel class of next generation polymyxin antibiotics. With widespread antibiotic resistance increasing rapidly and the rate of antibiotics development being alarmingly low, we are running out of effective antibiotics. One of the most urgent instances of this growing problem is the renewed interest in polymyxins as last-resort antibiotics, despite serious toxicities. Polymyxins are used for the treatment of infections caused by multi-drug resistant Gram-negative pathogens. However, a range of acute toxicities are linked to polymyxin treatment. Most problematic is the dose-limiting nephrotoxicity, requiring a careful balance between the dose required for efficacy while minimizing toxicity. However, in response to growing resistance to other classes of antibiotics, the use of polymyxins is increasing worldwide. In fact, over the past decade, the global use of polymyxins has doubled, placing them among the top five antibiotics prescribed in hospital settings. The increasingly frequent use of polymyxin antibiotics, despite their serious side effects, results in unnecessary pressure on healthcare systems and underscores the urgent need for safe alternatives. In the ERC PoC project NOVA we therefore set our to demonstrate the improved safety profile and potent antibacterial activity of a novel class of next generation polymyxin antibiotics recently discovered by our group in the context of the recently completed ERC CoG project NO-ESKAPE (#725523).

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

Specifically, we conducted the following activities: (i) optimization of the synthetic route used to prepare our next generation polymyxins, (ii) performed in vitro cell-based toxicity studies to demonstrate the reduced nephrotoxicity compared to clinically used polymyxins, (iii) demonstrated the in vivo efficacy of our next generation polymyxins in validated infection models, and (iv) perform an extensive analysis of the anti-Gram-negative antibiotics market including competitors and potential strategic partners.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

The results obtained in the PoC project are encouraging and will serve to pave the way for key-follow up studies aimed a further demonstrating the therapeutic potential of the next generation polymyxins developed. Specifically, a number of pre-clinical studies will be needed to ensure both the efficacy and safety of these compounds for future 1st in human trials. Significant outside investment will be necessary to further support such development.