Breaking resistance of pathogenic bacteria by chemical dysregulation

Projektinformationen

breakingBAC

ID Finanzhilfevereinbarung: 101096911

DOI

10.3030/101096911

EK-Unterschriftsdatum 5 Mai 2023

Startdatum 1 September 2023

Enddatum 31 August 2028

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

€ 2 499 785,00

EU-Beitrag

€ 2 499 785,00

Koordiniert durch

TECHNISCHE UNIVERSITAET MUENCHEN
Germany

Periodic Reporting for period 1 - breakingBAC (Breaking resistance of pathogenic bacteria by chemical dysregulation)

Berichtszeitraum: 2023-09-01 bis 2026-02-28

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

The rapid rise of multidrug-resistant bacteria represents one of the greatest challenges to modern medicine. Conventional antibiotics are increasingly losing their effectiveness, while the number of viable therapeutic targets has stagnated, leaving few options for treatment. To address this urgent problem, innovative approaches with entirely new modes of action are essential.
The breakingBAC project is designed to directly confront bacterial resistance by fundamentally disrupting bacterial physiology, rather than merely inhibiting individual targets. The strategy builds on a three-tiered concept: (1) activation of bacterial enzymes to provoke disruptive cellular processes, (2) induction of stress pathways that overwhelm protective responses, and (3) degradation of essential proteins critical for survival. By attacking bacteria through multiple, synergistic vulnerabilities, this approach is intended to bypass conventional resistance mechanisms and minimize the likelihood of new resistance emerging.
This program thus lays the groundwork for a new generation of antibiotics with unprecedented efficacy and durability. The ultimate goal is to translate these discoveries into urgently needed clinical candidates, contributing to the global fight against antimicrobial resistance and safeguarding the effectiveness of infection treatments for the future.

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

During the reporting period, the project delivered several breakthrough discoveries that directly advance its central objectives. Among the most significant is the identification of novel H. pylori antibiotics with a unique dual mode of action, simultaneously inducing cellular stress and inhibiting the bacterial stress response. This paradigm-shifting mechanism was further exemplified through work on metronidazole: by designing a synthetic alkyne probe, we uncovered a 60-fold increase in antibiotic potency and revealed an unprecedented dual mechanism, validated by co-crystal structures that clarified the binding mode.

Complementary efforts combined computational and chemical innovation. Artificial intelligence models tailored for antibiotic discovery generated de novo nitro-imidazole scaffolds, which were synthesized and confirmed as potent stress inducers with strong antibacterial activity. In parallel, isonitriles were exploited as versatile modulators of stress, with their chemical design enabling selective targeting of Fe-containing proteins. Finally, activation of bacterial hydrolases emerged as a novel and rational strategy for antibiotic development, with mechanistic studies of activation providing the structural foundation for future rational design.

Together, these advances not only highlight the innovative integration of experimental and AI-driven approaches, but also establish entirely new strategies for overcoming bacterial resistance and developing urgently needed next-generation antibiotics.

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)

There is a critical and growing need for novel antibiotics to address the global challenge of antimicrobial resistance. The discovery of a highly potent H. pylori antibiotic with demonstrated safety, efficacy, and an unprecedented dual mode of action represents a major step beyond current therapeutic options. Unlike existing treatments, this compound combines stress induction with inhibition of the bacterial stress response, offering a completely new mechanism that could overcome established resistance pathways.

To fully realize its translational potential, the compound now requires systematic pre-clinical testing to evaluate pharmacokinetics, toxicity, and efficacy in relevant infection models. Its development into a drug candidate would not only transform the treatment landscape for H. pylori infections but also provide a proof-of-concept for harnessing novel modes of action in antibiotic discovery, thereby setting the stage for broader impact across the field of anti-infective research.