RESEARCH ARTICLE Biocatalytic synthesis of diaryl disulphides and their bio-evaluation as potent inhibitors of drug-resistant Staphylococcus aureus Saima 1,2† | Isha Soni 3† | Aditya G. Lavekar 1 | Manjulika Shukla 3 | Danish Equbal 1 | Arun K. Sinha 1,2 | Sidharth Chopra 2,3 Enabling Technologies Strategy, Management & Health Policy Hit, Lead & Candidate Discovery Preclinical Research & Development Clinical Research Post-Market Research 1 Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India 2 Academy of Scientific and Innovative Research (AcSIR), New Delhi, India 3 Division of Microbiology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India Correspondence Arun K. Sinha, Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, Uttar Pradesh, India. Email: aksinha08@rediffmail.com and Sidharth Chopra, Division of Microbiology, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, Uttar Pradesh, India. Email: skchopra007@gmail.com Funding information This project was supported by CSIR-CDRI Internal funds Abstract Staphylococcus aureus is a WHO Priority II pathogen for its capability to cause acute to chronic infections and to resist antibiotics, thus severely impacting healthcare systems worldwide. In this context, it is urgently desired to discover novel molecules to thwart the continuing emer- gence of antimicrobial resistance. Disulphide containing small molecules has gained prominence as antibacterials. As their conventional synthesis requires tedious synthetic procedure and sometimes toxic reagents, a green and environmentally benign protocol for their synthesis has been developed through which a series of molecules were obtained and evaluated for antibac- terial activity against ESKAPE pathogen panel. The hit compound was tested for cytotoxicity against Vero cells to determine its selectivity index and time-kill kinetics was determined. The activity of hit was determined against a panel of S. aureus multi-drug resistant clinical isolates. Also, its ability to synergize with FDA approved drugs was tested as was its ability to reduce bio- film. We identified bis(2-bromophenyl) disulphide (2t) as possessing equipotent antimicrobial activity against S. aureus including MRSA and VRSA strains. Further, 2t exhibited a selectivity index of 25 with concentration-dependent bactericidal activity, synergized with all drugs tested and significantly reduced preformed biofilm. Taken together, 2t exhibits all properties to be positioned as novel scaffold for anti-staphylococcal therapy. KEYWORDS antibacterial, green, MRSA 1 | INTRODUCTION Staphylococcus aureus, a gram-positive coccus listed as a WHO Prior- ity two pathogen, is one of the most common causes of acute and complicated skin and skin structure infections to device-related bac- teremia and infective endocarditis (Baker & Alvi, 2004). It is typically a treatable infection but with continuing emergence of drug resistance, especially to Vancomycin, there is an urgent and unmet requirement to discover and develop novel antibiotics targeting S. aureus with a new mode of action, thus escaping existing antimicrobial resistance mechanisms. According to CDC, S. aureus accounts for 80,461 infec- tions and 11,285 deaths per year in the United States alone, which is more than HIV and TB combined, thus necessitating a dedicated drug discovery effort (Baud et al., 2012). Small molecules and their analogues have been used for the treat- ment of a vast array of diseases including microbial infections † These authors contributed equally to the manuscript. Received: 15 August 2018 Revised: 6 November 2018 Accepted: 28 November 2018 DOI: 10.1002/ddr.21507 Drug Dev Res. 2018;1–8. wileyonlinelibrary.com/journal/ddr © 2018 Wiley Periodicals, Inc. 1