Cross-Class Metallo-Β-Lactamase Inhibition by Bisthiazolidines Reveals Multiple Binding Modes
Cross-class metallo-β-lactamase inhibition by PNAS PLUS bisthiazolidines reveals multiple binding modes Philip Hinchliffea, Mariano M. Gonzálezb, Maria F. Mojicac,d, Javier M. Gonzáleze, Valerie Castillof, Cecilia Saizf, Magda Kosmopouloua, Catherine L. Tookea, Leticia I. Llarrullb, Graciela Mahlerf, Robert A. Bonomoc,d,g,h,i, Alejandro J. Vilab,1, and James Spencera,1 aSchool of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, United Kingdom; bFacultad de Ciencias Bioquímicas y Farmacéuticas, Instituto de Biología Molecular y Celular de Rosario Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Universidad Nacional de Rosario, 2000 Rosario, Argentina; cResearch Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH 44106; dDepartment of Biochemistry, Case Western Reserve University, Cleveland, OH 44106; eInstituto de Bionanotecnología, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Universidad Nacional de Santiago del Estero, G4206XCP Santiago del Estero, Argentina; fLaboratorio de Química Farmacéutica, Facultad de Química, Universidad de la República, Montevideo 11800, Uruguay; gDepartment of Pharmacology, Case Western Reserve University, Cleveland, OH 44106; hDepartment of Microbiology, Case Western Reserve University, Cleveland, OH 44106; and iDepartment of Molecular Biology, Case Western Reserve University, Cleveland, OH 44106 Edited by Gregory A. Petsko, Weill Cornell Medical College, New York, NY, and approved May 16, 2016 (received for review January 25, 2016) Metallo-β-lactamases (MBLs) hydrolyze almost all β-lactam antibi- molecule (Wat1) bridges/coordinates Zn1 and Zn2 in an arrange- otics and are unaffected by clinically available β-lactamase inhibi- ment that is suited to activate it as a nucleophile. tors (βLIs).
[Show full text]