Challenges and shortcomings of antibacterial discovery projects.

Objectives: Antibacterial drug discovery activities are essential for filling clinical pipelines with promising clinical candidates. Little information is available about the challenges and shortcomings of small companies and academic institutions in performing these important discovery tasks.

Methods: We performed a content analysis of 463 reviewer comments on 91 funding applications of antibacterial drug discovery projects submitted to two major global funders between 2016 and 2020 that had not proceeded further in the selection process. This quality assessment was complemented with the inputs (via e-mail) from a panel involving six antibiotic research and development (R&D) experts with long-standing expertise and experience in antibiotic drug discovery.

Results: Common critical comments of reviewers are grouped into three main categories: scientific and technical shortcomings, unclear potential societal impact, and insufficient capability and expertise of the project team regarding the R&D process. Insufficient characterization of in vitro activity and/or testing of the hits/leads and insufficient antibacterial activity were the most common critical comments. Other areas of concern were insufficient or lack of differentiation from available drugs or projects with a long R&D history, and the research team's insufficient knowledge of a structured streamlined R&D process as reflected in severe gaps in the expertise of the R&D team. Little appreciation for the problem of the emergence of target-based resistance, especially in single-target approaches, and little awareness of toxicological issues, including approaches with historical liabilities were also commonly mentioned. The shortcomings identified through the analysis of funding applications are echoed by the results of the expert panel.

Discussion: Our analysis identified an urgent need of strengthening the support for antibacterial drug discovery teams to help more projects reach such a quality to be eligible for global funders and private investors.