Antibotic resistance in Zn(II)-deficient environments: activation of metallo-beta-lactamases in the periplasm

• Autores: Meini, María Rocío; Gonzalez, Lisandro Javier; Vila, Alejandro Jose
• Año de publicación: 2013
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: Antibiotic Resistance; Metallo-Beta-Lactamase; Nutritional Immunity; Periplasm
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

Zn(II) is an essential metal ion in living organisms, playing a wide variety of roles as a structural, regulatory or catalytic cofactor in proteins. As is the case for most transition metal ions, high Zn(II) levels are toxic. Therefore, organisms have developed a series of mechanisms to regulate Zn(II) concentrations and to ensure proper metal uptake by metalloproteins. Bacterial pathogens require transition metal ions during infection to achieve an optimum colonization level and to activate a variety of virulence factors. This condition is exploited by the human host, which sequesters these metal ions in a process generally termed nutritional immunity. In addition to that, antibiotic resistance can also be affected by Zn(II) sequestration, as recently reported for a multidrug-resistant Acinetobacter baumannii strain, whose susceptibility to carbapenems was increased in the presence of a Zn(II)-chelating agent. The most outstanding resistance mechanism towards beta-lactam antibiotics involving Zn(II) ions is the expression of metallo-beta-lactamases (MBLs). Inhibitor design strategies for MBLs have been largely unsuccessful, mostly due to the structural diversity of their active sites. Many efforts have relied on a structural and biochemistry bases, but in vivo inhibition has not been effective. Novel strategies should consider Zn(II) uptake as a limiting step on MBL activation. Selective Zn(II) chelating schemes, reinforcing human host Zn(II) sequestering strategies, should be put into focus.
Fil: Meini, María Rocío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Gonzalez, Lisandro Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Vila, Alejandro Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Biología Molecular y Celular de Rosario; Argentina