title: Variations in the binding pocket of an inhibitor of the bacterial division protein FtsZ across genotypes and species.
abstract: The recent increase in antibiotic resistance in pathogenic bacteria calls for new approaches to drug-target selection and drug development. Targeting the mechanisms of action of proteins involved in bacterial cell division bypasses problems associated with increasingly ineffective variants of older antibiotics; to this end, the essential bacterial cytoskeletal protein FtsZ is a promising target. Recent work on its allosteric inhibitor, PC190723, revealed in vitro activity on Staphylococcus aureus FtsZ and in vivo antimicrobial activities. However, the mechanism of drug action and its effect on FtsZ in other bacterial species are unclear. Here, we examine the structural environment of the PC190723 binding pocket using PocketFEATURE, a statistical method that scores the similarity between pairs of small-molecule binding sites based on 3D structure information about the local microenvironment, and molecular dynamics (MD) simulations. We observed that species and nucleotide-binding state have significant impacts on the structural properties of the binding site, with substantially disparate microenvironments for bacterial species not from the Staphylococcus genus. Based on PocketFEATURE analysis of MD simulations of S. aureus FtsZ bound to GTP or with mutations that are known to confer PC190723 resistance, we predict that PC190723 strongly prefers to bind Staphylococcus FtsZ in the nucleotide-bound state. Furthermore, MD simulations of an FtsZ dimer indicated that polymerization may enhance PC190723 binding. Taken together, our results demonstrate that a drug-binding pocket can vary significantly across species, genetic perturbations, and in different polymerization states, yielding important information for the further development of FtsZ inhibitors.
authors: Department of Bioengineering, Stanford University, Stanford, California, United States of America.
authors: Amanda
authors: A
authors: Miguel
authors: Department of Bioengineering, Stanford University, Stanford, California, United States of America.
authors: Jen
authors: J
authors: Hsin
authors: Department of Bioengineering, Stanford University, Stanford, California, United States of America.
authors: Tianyun
authors: T
authors: Liu
authors: Department of Bioengineering, Stanford University, Stanford, California, United States of America.
authors: Grace
authors: G
authors: Tang
authors: Department of Bioengineering, Stanford University, Stanford, California, United States of America.
authors: Russ B
authors: RB
authors: Altman
authors: Department of Bioengineering, Stanford University, Stanford, California, United States of America; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America.
authors: Kerwyn Casey
authors: KC
authors: Huang
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D056004:Molecular Dynamics Simulation; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013844:Thiazoles / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D001426:Bacterial Proteins; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; C531944:PC190723; D011725:Pyridines; D013844:Thiazoles