Dharra, RRadhakrishnan,V.SPrasad, TThakur, ZCirillo, J.DSheoran, APandey, A.KKulharia, MaheshMehta P.K.2019-09-032024-08-132019-09-032024-08-132019Dharra, R., Radhakrishnan,V.S and Prasad, T., et.alEvaluation of in silico designed inhibitors targeting MelF (Rv1936) against Mycobacterium marinum within macrophages.9(1).10.1038/s41598-019-46295-52045232210.1038/s41598-019-46295-5https://kr.cup.edu.in/handle/32116/2384We recently identified inhibitors targeting Mycobacterium marinum MelF (Rv1936) by in silico analysis, which exhibited bacteriostatic/bactericidal activity against M. marinum and M. tuberculosis in vitro. Herein, we evaluated the effect of best four inhibitors (# 5175552, # 6513745, # 5255829, # 9125618) obtained from the ChemBridge compound libraries, on intracellular replication and persistence of bacteria within IFN-γ activated murine RAW264.7 and human THP-1 macrophages infected with M. marinum. Inhibitors # 5175552 and # 6513745 significantly reduced (p < 0.05) the intracellular replication of bacilli during day 7 post-infection (p.i.) within RAW264.7 and THP-1 macrophages infected at multiplicity of infection (MOI) of ~1.0. These observations were substantiated by electron microscopy, which revealed the protective effect of # 5175552 in clearing the bacilli inside murine macrophages. Strikingly, # 6513745 displayed synergism with isoniazid against M. marinum in murine macrophages, whereas # 5175552 significantly suppressed (p < 0.05) the persistent bacilli during day 10–14 p.i. in infected RAW264.7 and THP-1 macrophages (MOI of ~ 0.1). Moreover, # 5175552 and # 6513745 were non-cytotoxic to host macrophages at both 1X and 5X MIC. Further validation of these inhibitors against M. tuberculosis-infected macrophages and animal models has potential for development as novel anti-tubercular agents. © 2019, The Author(s).enArticlehttps://www.nature.com/articles/s41598-019-46295-5