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 anthraquinonebased 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 noncompetitive inhibition, reduced the turnover (K cat ) and catalytic efficiency (K m /K cat ) of MNase with an IC 50 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.