An allosteric inhibitor of Mycobacterium tuberculosis ArgJ: Implications to a novel combinatorial therapy
Authors: Ashalatha S Mamidi
Ananya Ray
Raju S Rajmani
Archita Mishra
Avadhesha Surolia
Rajanya Roy
Journal: EMBO Molecular Medicine (2018)
Discipline: CLINICAL MEDICINE
Keywords: Mycobacterium tuberculosis; Ornithine acetyltransferase; combinatorial therapy; drug repurposing; infectious disease.
Affiliations: Molecular Biophysics Unit Indian Institute of Science Bangalore India, Microbiology and Cell Biology CIDR Indian Institute of Science Bangalore India

Abstract:  The existing treatment regime against tuberculosis is not adequate, and novel therapeutic interventions are required to target Mycobacterium tuberculosis (Mtb) pathogenesis. We report Pranlukast (PRK) as a novel allosteric inhibitor of Mtb's arginine biosynthetic enzyme, Ornithine acetyltransferase (MtArgJ). PRK treatment remarkably abates the survival of free as well as macrophage-internalized Mtb, and shows enhanced efficacy in combination with standard-of-care drugs. Notably, PRK also reduces the 5-lipoxygenase (5-LO) signaling in the infected macrophages, thereby surmounting an enhanced response against intracellular pathogen. Further, treatment with PRK alone or with rifampicin leads to significant decrease in Mtb burden and tubercular granulomas in Mtb-infected mice lungs. Taken together, this study demonstrates a novel allosteric inhibitor of MtArgJ, which acts as a dual-edged sword, by targeting the intracellular bacteria as well as the bacterial pro-survival signaling in the host. PRK is highly effective against in vitro and in vivo survival of Mtb and being an FDA-approved drug, it shows a potential for development of advanced combinatorial therapy against tuberculosis. 

Retracted: No

PubPeer comments:
  , 
 EMBO Mol Med is looking into this issue. , 
 Dear Colleague, We sincerely thank you for your efforts in pointing out this error in the representative histopathology image in our article. This image in figure 8i is only for the representative purpose (as mentioned in the legend) and the error must have happened during the final assembly of the figure. However, all the original images for the corresponding histopathology slides are already provided in the appendix fig. S10 and S11 (as mentioned in the legend of fig. 8). We are in contact with the journal and are in process to do the required corrections. Meanwhile, we request the readers to refer the appendix fig. S10 and S11 for all the original histopathology images in the article. We sincerely apologise for the inconvenience caused. Just to clarify for the non-familiar readers, all these images have the same staining, H E (haemotoxylin and eosin) stain to visualize the cellular structures, where Eosin being an acidic dye stain the cytoplasm pink and haemotoxylin component being basic, stains the nucleus purple. We also thank our colleagues at Pubpeer for notifying us about this through a recent e-mail. Once corrected, we will notify at this portal as well, very soon. Regards, Archita Mishra and Avadhesha Surolia , 
 In addition to the 2 sets of duplicated panels, there is a possible duplication between a panel in Figure S11 (rifampicin treated) and Figure 8i (PRK treated). Shown here in blue boxes. There is another duplication (shown in orange) but that one appears to show the same treatment. Together with the observations pointed out in #1, that means that 3 out of the 4 panels in Figure 8i are incorrect.  , 
 Dear Reader, We realized our mistake in the figure 8i and S11 while doing the correction for #1 and have already provided all the original source files to the journal for necessary corrections to be made. The journal has reviewed the files and a correction will be posted in a couple of weeks. However, we would like to point out that regarding point #4: yes the blue box is a mistake and have been addressed in the correction, while the orange box is not a mistake as we have already mentioned in the figure legend of fig. 8i that  these are the representative images and the original images given in supplementary fig. S10 and S11 , where we have provided both 100x and 400x magnification for these sections. The corrected version will further clarify all this, as we totally understand the confusion this may have caused. Thanks once again for your time and efforts and our apologies for the inconvenience this may have caused. We will post the corrections here at Pubpeer once it s online and would be happy to assist for further clarifications. Regards, Archita Mishra and Avadhesha Surolia , 
 Prof. Surolia, I am ashamed to have worked with you. S . Sanker , 
 Correction, October 2019: https: www.embopress.org doi full 10.15252 emmm.201911209  The journal became aware of inconsistencies observed between Fig 8I, and Appendix Figs S10 and S11 in April 2019. In response to our request to provide source data and clarifications, the authors state that the labeling errors in Fig 8I, which displays representative images from Appendix Figs S10 and S11, were introduced during revision. The authors amended the labeling in Fig 8I, provided scale bars in 8I, S10, and S11, and corrected the representative image for the Rif + PRK image in Fig 8I (iv). Source data for these figures are available for download with this notice. This corrigendum does not affect the conclusions of the paper. The authors apologize for their oversight and any confusion it may have caused. ,