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{"title":"Combined StructuralnAnalysis and Molecular DynamicsnReveal Penicillin-Binding Protein Inhibition Mode with β‑Lactones","authors":"ParkerL. Flanders (13883275), Carlos Contreras-Martel (173851), Nathaniel W. Brown (13883278), Joshua D. Shirley (4521907), Alexandre Martins (1429057), Kelsie N. Nauta (13883281), Andréa Dessen (2056177), Erin E. Carlson (1371462), Elizabeth A. Ambrose (6910985)","doi":"10.1021/acschembio.2c00503.s001","DOIUrl":"https://doi.org/10.1021/acschembio.2c00503.s001","url":null,"abstract":"β-Lactam antibiotics comprise one of the most widelynusedntherapeutic classes to combat bacterial infections. This general scaffoldnhas long been known to inhibit bacterial cell wall biosynthesis byninactivating penicillin-binding proteins (PBPs); however, bacterialnresistance to β-lactams is now widespread, and new strategiesnare urgently needed to target PBPs and other proteins involved innbacterial cell wall formation. A key requirement in the identificationnof strategies to overcome resistance is a deeper understanding ofnthe roles of the PBPs and their associated proteins during cell growthnand division, such as can be obtained with the use of selective chemicalnprobes. Probe development has typically depended upon known PBP inhibitors,nwhich have historically been thought to require a negatively chargednmoiety that mimics the C-terminus of the PBP natural peptidoglycannsubstrate, d-Ala-d-Ala. However, we have identifiedna new class of β-lactone-containing molecules that interactnwith PBPs, often in an isoform-specific manner, and do not incorporatenthis C-terminal mimetic. Here, we report a series of structural biologynexperiments and molecular dynamics simulations that we utilized tonevaluate specific binding modes of this novel PBP inhibitor class.nIn this work, we obtained <2 Å resolution X-ray structuresnof four β-lactone probes bound to PBP1b from <i>Streptococcusnpneumoniae</i>. Despite their diverging recognition modes beyondnthe site of covalent modification, these four probes all efficientlynlabeled PBP1b, as well as other PBPs from <i>S</i>. <i>pneumoniae</i>. From these structures, we analyzed protein–ligandninteractions and characterized the β-lactone-bound active sitesnusing <i>in silico</i> mutagenesis and molecular dynamics.nOur approach has clarified the dynamic interaction profile in thisnseries of ligands, expanding the understanding of PBP inhibitor binding.","PeriodicalId":521562,"journal":{"name":"Figshare","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147881524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}