Bioreductively Activated Reactive Oxygen Species (ROS) Generators as MRSA Inhibitors

Vinayak S Khodade; Mallojjala Sharath Chandra; Ankita Banerjee; Surobhi Lahiri; Mallikarjuna Pulipeta; Radha Rangarajan; Harinath Chakrapani

doi:10.1021/ml5001118

Bioreductively Activated Reactive Oxygen Species (ROS) Generators as MRSA Inhibitors

ACS Med Chem Lett. 2014 May 18;5(7):777-81. doi: 10.1021/ml5001118. eCollection 2014 Jul 10.

Authors

Vinayak S Khodade¹, Mallojjala Sharath Chandra¹, Ankita Banerjee², Surobhi Lahiri², Mallikarjuna Pulipeta², Radha Rangarajan², Harinath Chakrapani¹

Affiliations

¹ Indian Institute of Science Education and Research Pune , Dr. Homi Bhabha Road, Pune, 411008 Maharashtra, India.
² Vitas Pharma Research Private Limited, Technology Business Incubator, University of Hyderabad , C. R. Rao Road, Gachibowli, Hyderabad 500046, India.

Abstract

The number of cases of drug resistant Staphylococcus aureus infections is on the rise globally and new strategies to identify drug candidates with novel mechanisms of action are in urgent need. Here, we report the synthesis and evaluation of a series of benzo[b]phenanthridine-5,7,12(6H)-triones, which were designed based on redox-active natural products. We find that the in vitro inhibitory activity of 6-(prop-2-ynyl)benzo[b]phenanthridine-5,7,12(6H)-trione (1f) against methicillin-resistant Staphylococcus aureus (MRSA), including a panel of patient-derived strains, is comparable or better than vancomycin. We show that the lead compound generates reactive oxygen species (ROS) in the cell, contributing to its antibacterial activity.

Keywords: DNA damage; Drug resistance; MRSA; RecA; reactive oxygen species; superoxide radical.