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

MEINI MR; GONZÁLEZ LJ; VILA AJ

FUTURE MICROBIOLOGY

FUTURE MEDICINE LTD

Lugar: Londres; Año: 2013 vol. 8 p. 1 - 3

1746-0913

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 by sequestering these metal ions in a process generally termed ?nutritional immunity?. Antibiotic resistance can also be affected by Zn(II) sequestration, as recently reported for a multidrug resistant Acinetobacter baumanni whose susceptibility towards carbapenems was increased in the presence of a Zn(II) chelating agent. The most outstanding Zn(II) dependant resistance mechanism towards beta-lactam antibiotics is the expression of metallo-beta-lactamases (MBLs). MBLs fold and acquire the essential Zn(II) ions in the periplasmic space of Gram negative bacteria. The process defining the binding preference for Zn(II) over other divalent cations is strictly linked to cellular compartment. Although metallochaperones insert the correct metal into some proteins, they have not been found for the vast majority, and the view is that most metalloproteins acquire their metals directly from cellular pools. Opposite to the cytoplasm, the periplasmic concentration of metals, at least in E. coli, is highly sensitive to the metal composition of the growth medium. These conclusions highlight then the relevance of the Zn(II) availability in the external milieu in regulating antibiotic resistance. The amount of available Zn(II) in biological fluids is a complex issue under debate, which results from a complex equilibrium among different chelating agents. Thus, periplasmic Zn(II) levels are limited by the external medium and by the strict requirement from the bacterial cytoplasm. Under this scenario, MBLs are involved in a tight competition for the available periplasmic Zn(II), which requires high affinities toward this metal ion. Inhibitor design strategies for MBLs have been largely unsuccessful, mostly based on their structural diversity. This picture suggest that novel strategies should consider selective Zn(II) chelating schemes.