Combined Structural Analysis and Molecular Dynamics Reveal Penicillin-Binding Protein Inhibition Mode with β‑Lactones

• Published in: ACS chemical biology 2022-11, Vol.17 (11), p.3110-3120
• Main Authors: Flanders, Parker L., Contreras-Martel, Carlos, Brown, Nathaniel W., Shirley, Joshua D., Martins, Alexandre, Nauta, Kelsie N., Dessen, Andréa, Carlson, Erin E., Ambrose, Elizabeth A.
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacterial Proteins; Bacterial Proteins - metabolism; beta-Lactams; beta-Lactams - metabolism; Biochemistry, Molecular Biology; Lactones; Lactones - pharmacology; Life Sciences; Ligands; Molecular Dynamics Simulation; Penicillin-Binding Proteins; Penicillin-Binding Proteins - metabolism; Pharmaceutical sciences; Pharmacology; Streptococcus pneumoniae; Streptococcus pneumoniae - chemistry; Structural Biology
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/acschembio.2c00503

β-Lactam antibiotics comprise one of the most widely used therapeutic classes to combat bacterial infections. This general scaffold has long been known to inhibit bacterial cell wall biosynthesis by inactivating penicillin-binding proteins (PBPs); however, bacterial resistance to β-lactams is now widespread, and new strategies are urgently needed to target PBPs and other proteins involved in bacterial cell wall formation. A key requirement in the identification of strategies to overcome resistance is a deeper understanding of the roles of the PBPs and their associated proteins during cell growth and division, such as can be obtained with the use of selective chemical probes. Probe development has typically depended upon known PBP inhibitors, which have historically been thought to require a negatively charged moiety that mimics the C-terminus of the PBP natural peptidoglycan substrate, d-Ala-d-Ala. However, we have identified a new class of β-lactone-containing molecules that interact with PBPs, often in an isoform-specific manner, and do not incorporate this C-terminal mimetic. Here, we report a series of structural biology experiments and molecular dynamics simulations that we utilized to evaluate specific binding modes of this novel PBP inhibitor class. In this work, we obtained