Jani Bolla
Department of Biology, University of Oxford, UK
Next-generation antibiotics: Exploring the bacterial cell envelope for new targets
The rapid spread of drug-resistant pathogens, and the declining discovery of new antibiotics, has created a global health crisis and heightened interest in the search for novel antibiotics. Consistently, over the past decade, there has been a significant increase in the identification of novel antibiotics using innovative methodologies ranging from the ability to cultiva (1-4). These advancements are considerably enhancing the pace of antibiotic discovery, including those that are active against Gram-positive bacteria without detectable resistance, e.g., teixobactin, and those that are active against Gram-negative pathogenic bacteria, e.g., darobactin. A major obstacle in advancing these newly identified cell envelope targeting molecules and also for those modified existing antibiotics (5), however, is the task of elucidating their mechanisms of action (MoA). Such understanding can foster precision therapeutics, resistance abatement strategies, and the development of new analogues. In this talk, I will present how native mass spectrometry can be used to understand the MoA of antibiotics, especially for those targeting the lipidic substrates and membrane proteins that are involved in the cell envelope biogenesis (6,7). Furthermore, I will also present our latest findings in characterising the lipopolysaccharide transport system in pathogenic Gram-negative bacteria using an integrative structural biology approach (8,9,) opening up new avenues for developing next-generation antibiotics.
References
- 1 Nat Microbiol 2019, 4:2498-2510
- 2 eLife 2021, 10:e64774
- 3 Cell 2020, 181:475-483
- 4 Cell 2023, 186:4059-4073
- 5 PNAS 2023, 120:e2208737120
- 6 Nat Chem 2018, 10:363-371
- 7 Nat Commun 2022, 13:2278
- 8 Nat Chem Biol 2021, 17:187-195
- 9 Chem Commun 2021, 57:10747-10750