Anthraquinone-Based Ligands as MNase Inhibitors: Insights from Inhibition Studies and Generation of a Payload Nanocarrier for Potential Anti-MRSA Therapy.

Abstract

The present study highlights the prospect of an anthraquinone-based ligand (C1) as an inhibitor of micrococcal nuclease (MNase) enzyme secreted by Staphylococcus aureus. MNase inhibition rendered by 5.0 μM C1 was ∼96 % and the ligand could significantly distort the β-sheet conformation present in MNase. Mechanistic studies revealed that C1 rendered non-competitive inhibition, reduced the turnover (Kcat ) and catalytic efficiency (Km /Kcat ) of MNase with an IC50 value of 323 nM. C1 could also inhibit nuclease present in the cell-free supernatant (CFS) of a methicillin-resistant Staphylococcus aureus (MRSA) strain. A C1-loaded human serum albumin (HSA)-based nanocarrier (C1-HNC) was developed, which was amicable to protease-triggered release of payload in presence of the CFS of an MRSA strain. Eluates from C1-HNC could effectively reduce the rate of MNase-catalyzed DNA cleavage. The non-toxic nature of C1-HNC in conjunction with the non-competitive mode of MNase inhibition rendered by C1 offers interesting therapeutic prospect in alleviation of MRSA infections.