Metallo-β-lactamases withstand low Zn(II) conditions by tuning metal-ligand interactions.
A number of multiresistant bacterial pathogens inactivate antibiotics by producing Zn(II)-dependent β-lactamases. We show that metal uptake leading to an active dinuclear enzyme in the periplasmic space of Gram-negative bacteria is ensured by a cysteine residue, an unusual metal ligand in oxidizing environments. Kinetic, structural and affinity data show that such Zn(II)-cysteine interaction is an adaptive trait that tunes the metal binding affinity, thus enabling antibiotic resistance at restrictive Zn(II) concentrations.
Instituto de Biología Molecular y Celular de Rosario, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina.
Javier M
JM
González
María-Rocío
MR
Meini
Pablo E
PE
Tomatis
Francisco J
FJ
Medrano Martín
Julia A
JA
Cricco
Alejandro J
AJ
Vila
D000222:Adaptation, Physiological; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D008024:Ligands; D008958:Models, Molecular; D010084:Oxidation-Reduction; D019897:Periplasm; D011485:Protein Binding; D011487:Protein Conformation; D015032:Zinc / Q000737:chemistry / Q000378:metabolism*; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D008024:Ligands; D001618:beta-Lactamases; D015032:Zinc