STAR · Structural biology tools for Antibiotic Research

Antimicrobial resistance (AMR) is escalating due to multidrug-resistant (MDR) bacteria and a dwindling antibiotic pipeline and is projected to cause up to 10 million deaths annually by 2050. Lipid-targeting (LT) antibiotics such as daptomycin and polymyxins combat MDR infections by disrupting bacterial membranes, yet their mechanisms remain unclear due to major technical challenges for structural biology. This knowledge gap hinders the development of next-generation LT-antibiotics with improved efficacy and safety profiles.STAR will positively impact structural biology capabilities by channeling the potential of Solid-State Nuclear Magnetic Resonance (ssNMR) spectroscopy to provide atomic-level insights into LT-antibiotic interactions under physiologically relevant conditions. By optimizing the scaled production of pure, 13C/15N-labeled phospholipids, STAR will overcome key technical hurdles that have constrained ssNMR’s application in antibiotic research, dramatically boosting ssNMR sensitivity and enabling selective detection of specific lipid interactions in complex membranes. This breakthrough will allow high-resolution visualization of drug-lipid interactions of antibiotics, enabling a transformative platform to elucidate the mechanism of action (MoA) of LT-antibiotics and guide the development of potent new derivatives.To bridge a critical knowledge gap in antibiotic research, STAR will optimize the scalable bacterial production of 13C/15N-labeled phospholipids for higher yields and refine purification techniques to enhance ssNMR signal sensitivity at larger scales. Additionally, STAR will evaluate commercial feasibility and intellectual property strategies to facilitate ssNMR’s market entry. By enabling deeper molecular insights into LT-antibiotics, STAR will accelerate antibiotic research and discovery, addressing the urgent threat of AMR.