Inhibitory effect of polyoxotungstates on the production of penicillin-binding proteins and beta-lactamase against methicillin-resistant Staphylococcus aureus.

In our continuous work on the enhancement of the antibacterial activity of beta-lactam antibiotics against the cells of methicillin-resistant Staphylococcus aureus (MRSA) strains by Keggin-structural polyoxotungstates and their lacunary species, Wells-Dawson, double-Keggin, and Keggin-sandwich polyoxotungstates are also found to be synergistic but highly cytotoxic. The coexistence of polylysine or protamine sulphate decreased the synergistic potency of the polyoxotungstates, due to their electrostatic interaction with negatively charged polyoxotungstates. Inductively coupled plasma atomic emission spectrometry (ICP) analysis of the polyoxotungstate-treated cells indicated that the polyoxotungstates uptaken in the cell are preferentially located at the membrane fraction with intact composition. The polyoxotungstates depressed not only the production of PBP2', but also the production of beta-lactamase which hydrolyzes beta-lactam antibiotics on the membrane. This leads to the synergistic effect of polyoxotungstates against the MRSA cells in the coexistence of beta-lactam antibiotics which have high affinities to PBPs 1-4. MRSA cells which were modified to be susceptible to beta-lactam antibiotics during incubation in the presence of polyoxotungstates recovered their resistance to beta-lactam antibiotics when they were subcultured in the absence of the polyoxotungstate.