Validating fatty acid synthesis enzymes as targets for antibiotics against Pseudomonas aeruginosa and other Gram-negative bacteria.

Antibiotic resistance is becoming a serious global health threat. As bacteria evolve to resist our current medicines, infections that were once easy to treat are becoming deadly again. The World Health Organization (WHO) has identified a list of dangerous bacteria where we urgently need new antibiotics. Unfortunately, most antibiotics being developed today are just slightly modified versions of old ones—and bacteria are already learning how to resist them too. To truly solve this problem, we need to find new ways to attack bacteria. That means discovering new weak spots in bacteria and designing antibiotics that can reach and disable those targets. This project aims to do just that. Our team of international scientists is working together to: - Investigate two specific bacterial enzymes to learn if they are good targets for future antibiotics. - Contribute to increasing our understanding of how drug molecules get inside bacteria, which is one of the biggest challenges in antibiotic development. We’re focusing on three types of harmful bacteria: Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae. These are all “Gram-negative” bacteria, which are especially tough to treat because of their strong outer defenses. Our strategy is to study two key enzymes these bacteria use to make fatty acids—molecules they need to survive. Using a combination of techniques, we’ll design and test new compounds that can block these enzymes. At the same time, we’ll study how these compounds enter the bacteria, so we can make sure they actually reach their targets. By combining chemistry, biology, and drug design, this project will not only help us move forward on the road to finding new antibiotics—it will also give us valuable insights into how to design better antibiotics in the future.

There is an urgent need for new antibiotics to prevent the looming crisis of antimicrobial resistance and WHO has published a list of bacteria for which antibiotics are in high demand and urged that research and drug discovery efforts are directed toward these. Antibiotics are a prerequisite for modern medicine, however, most of the compounds in clinical development are not fit for purpose at they are derivatives of already known antibiotics and therefore have cross-resistance with existing agents. To tackle this crisis, we need fundamental knowledge on new targets for antibiotics, and we need compounds that can get into bacteria and work on these targets. This project will address this 1) by delivering potent inhibitors on two proposed bacterial protein targets to establish if they are promising targets for future antibiotics and 2) by establishing relationships between compound properties and uptake in bacteria. To reach these highly ambitious goals, we have assembled an interdisciplinary and international team of experts in antibiotic drug discovery, protein dynamics, structure-based drug design, covalent enzyme inhibition, organic synthesis and medicinal chemistry. We will explore two essential enzymes involved in fatty acid synthesis in Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae, Gram-negative bacteria for which WHO has stated that new antibiotics are critically needed. We will use a structure-based approach to develop potent inhibitors for chemical target validation. This process will be guided by experimental data about uptake into bacteria to ensure that our compounds reach their targets, a critical step in chemical target validation. Through this we will provide crucial information to advance our understanding of the compound properties that governs uptake in Gram-negative bacteria. This will deliver far-reaching insights, not only for the studied target but antibiotic drug discovery in general.