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Background  Resuscitation promoting factors (RPF) are secreted proteins involved in reactivation of dormant actinobacteria, including  Mycobacterium tuberculosis . They have been considered as prospective targets for the development of new anti-tuberculosis drugs preventing reactivation of dormant tubercle bacilli, generally associated with latent tuberculosis. However, no inhibitors of Rpf activity have been reported so far. The goal of this study was to find low molecular weight compounds inhibiting the enzymatic and biological activities of Rpfs.    Methodology/Principal Findings  Here we describe a novel class of 2-nitrophenylthiocyanates (NPT) compounds that inhibit muralytic activity of Rpfs with IC 50  1–7 µg/ml. Fluorescence studies revealed interaction of active NPTs with the internal regions of the Rpf molecule. Candidate inhibitors of Rpf enzymatic activity showed a bacteriostatic effect on growth of  Micrococcus luteus  (in which Rpf is essential for growth protein) at concentrations close to IC 50 . The candidate compounds suppressed resuscitation of dormant (“non-culturable”) cells of  M. smegmatis  at 1 µg/ml or delayed resuscitation of dormant  M. tuberculosis  obtained in laboratory conditions at 10 µg/ml. However, they did not inhibit growth of active mycobacteria under these concentrations.    Conclusions/Significance  NPT are the first example of low molecular weight compounds that inhibit the enzymatic and biological activities of Rpf proteins.

Finding of the Low Molecular Weight Inhibitors of Resuscitation Promoting Factor Enzymatic and Resuscitation Activity