Next Generation Polymyxin Antibiotics: Optimization and Validation

Project Information

NOVA

Grant agreement ID: 101082241

DOI

10.3030/101082241

Project closed

EC signature date 18 October 2022

Start date 1 November 2022

End date 30 April 2024

Funded under

• European Research Council (ERC)

Total cost

No data

EU contribution

€ 150 000,00

Coordinated by

UNIVERSITEIT LEIDEN
Netherlands

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

Reporting period: 2022-11-01 to 2024-04-30

Summary of the context and overall objectives of the project

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).

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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.