Cross-class metallo-β-lactamase inhibition by bisthiazolidines reveals multiple binding modes

PHILIP HINCHLIFFE; JAVIER MARCELO GONZÁLEZ; MARIANO GONZALEZ; MARÍA MOJICA

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

NATL ACAD SCIENCES

Lugar: Washington DC, USA; Año: 2016 vol. 113 p. 3745 - 3754

0027-8424

Bacterial diseases remain a huge burden on healthcare worldwide, with the emergence and re-emergence of strains resistant to currently used antibiotics posing an increasing clinical threat. Metallo-ß-lactamases (MBLs) are key determinants of antibiotic resistance because they hydrolyze almost all ß-lactam antibiotics and are unaffected by currently available ß-lactamase inhibitors (ßLIs). The structural diversity between MBLs has proved problematic when designing ßLIs effective against all MBL targets. Here we show a series of small compounds, bisthiazolidines, which act as inhibitors of all MBL types, restoring the efficacy of currently used antibiotics against resistant bacterial strains producing different MBLs. High-resolution crystal structures reveal how diverse MBLs are inhibited by the unexpected versatility of bisthiazolidine binding, raising implications for future ßLI design.