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.
