Unveiling DprE1 as a Key Target in the Fight against Tuberculosis: Insights and Perspectives on Developing Novel Antimicrobial Agents
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors
Line 57: While most bacteria can be classified as either "gram-positive" or "gram-negative," a. Authors should endeavor to write the word gram as Gram throughout the entire manuscript.
Line 63: The mycobacterial cell wall exhibits distinct characteristics that set it apart from other > The mycobacterial cell wall exhibits distinct characteristics that sets it apart from other
Line 100: As previously noted, arabinogalactan plays a crucial role in the structure of mycobacteria. Did the authors mean structure of mycobacterial cell wall?
Line 101: Inhibiting its synthesis has been demonstrated to be fatal for Mycobacterium, particularly Mycobacterium tuberculosis (Mtb). Authors need to be explicit on this. Is this in vivo or ex vivo?
2.2. DprE1/DprE2 Complex
Line 153: DprE1 is recognized as an established putative target for TB treatment, as evidenced by various patents, patent applications. Since the authors are making a case about DprE1 as a promising target in the fight against tuberculosis, I believe that it is important to visualize a graph showing average number of these patents over time.
Line 462: Mycobacterium tuberculosis > Mycobacterium tuberculosis (should be italicized).
Author Response
Thank you for all comments, corrections and suggestions. They have strengthened the discussion on the challenge of developing anti-tuberculosis agents.
Line 57: While most bacteria can be classified as either "grampositive" or "gram-negative," a. Authors should endeavor to write the word gram as Gram throughout the entire manuscript.
Authors’ response: The word "Gram" is written consistently throughout the entire manuscript.
Line 63: The mycobacterial cell wall exhibits distinct characteristics that set it apart from other > The mycobacterial cell wall exhibits distinct characteristics that sets it apart from other.
Authors’ response: The word "sets" is corrected
Line 100: As previously noted, arabinogalactan plays a crucial role in the structure of mycobacteria. Did the authors mean structure of mycobacterial cell wall?
Authors’ response: We mean structure of mycobacterial cell wall
Line 101: Inhibiting its synthesis has been demonstrated to be fatal for Mycobacterium, particularly Mycobacterium tuberculosis (Mtb). Authors need to be explicit on this. Is this in vivo or ex vivo?
Authors’ response: The explanation is done in the text
2.2. DprE1/DprE2 Complex
Line 153: DprE1 is recognized as an established putative target for TB treatment, as evidenced by various patents, patent applications. Since the authors are making a case about DprE1 as a promising target in the fight against tuberculosis, I believe that it is important to visualize a graph showing average number of these patents over time.
Authors’ response: A figure of DprE1 inhibitor patents from 2012 is added
Line 462: Mycobacterium tuberculosis > Mycobacterium tuberculosis (should be italicized).
Authors’ response: Mycobacterium tuberculosis is italicized
As other modifications have been made, the modifications are underlined in yellow in the Word version of the manuscript.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsThank you for allowing me to review this interesting manuscript. It is generally well-written and contains up-to-date information on DprE1.
Spell out abbreviations on their first mention. Thus, “DprE1/DprE2” in the abstract should be spelt out as “decaprenylphosphoryl-β-D-ribose oxidase (DprE1)/ decaprenylphosphoryl-2-keto-beta-D-erythropentose reductase (DprE2).”
Line 11: what do the authors mean by “undeserved” regions? I believe the term “underdeveloped” or “developing” is more appropriate.
Line 11: “Mtb” has to be spelt out since it is encountered for the first time in the manuscript. Subsequently, there is no more need to spell it out again (review lines 61 and 103).
Line 29: mention that the first 2 months are essentially the intensive treatment phase and the remaining 4 months are the continuation phase.
Under subsection 2.1, it can be explained that DprE1, which stands for decaprenylphosphoryl-β-D-ribose 2'-epimerase is actually composed of two isoforms, decaprenylphosphoryl-β-D-ribose oxidase (DprE1) and decaprenylphosphoryl-2-keto-beta-D-erythropentose reductase (DprE2).
Lines 164 and 188 contain the exact same subheading (i.e. DprE1 Covalent Inhibitors).
Line 304: “CYP” should be spelt out as “cytochrome P450” during its initial mention.
The conclusion is insightful and aptly summarise the topic.
Reference no. 72 is either incomplete or not supposed to be present.
Author Response
Thank you for all comments, corrections and suggestions. They have strengthened the discussion on the challenge of developing anti-tuberculosis agents.
Spell out abbreviations on their first mention. Thus, “DprE1/DprE2” in the abstract should be spelt out as “decaprenylphosphoryl-β-Dribose oxidase (DprE1)/ decaprenylphosphoryl-2-keto-beta-Derythropentose reductase (DprE2).”
Authors’ response: DprE1/DprE2 is spelt out as “decaprenylphosphoryl-β-Dribose oxidase (DprE1)/ decaprenylphosphoryl-2-keto-beta-Derythropentose reductase (DprE2)”.
Authors’ response: DprE1/DprE2 is spelled out as 'decaprenylphosphoryl-β-D-ribose oxidase (DprE1)/decaprenylphosphoryl-2-keto-β-D-erythropentose reductase (DprE2)
Line 11: what do the authors mean by “undeserved” regions? I believe the term “underdeveloped” or “developing” is more appropriate.
Authors’ response: The term “underdeveloped” is used appropriately
Line 11: “Mtb” has to be spelt out since it is encountered for the first time in the manuscript. Subsequently, there is no more need to spell it out again (review lines 61 and 103).
Authors’ response: Mycobacterium tuberculosis is spelt out in the abstract and the introduction. Subsequently, the abbreviation Mtb is used
Line 29: mention that the first 2 months are essentially the intensive treatment phase and the remaining 4 months are the continuation phase.
Authors’ response: Precise details on the two phases of treatment have been added.
Under subsection 2.1, it can be explained that DprE1, which stands for decaprenylphosphoryl-β-D-ribose 2'-epimerase is actually composed of two isoforms, decaprenylphosphoryl-β-D-ribose oxidase (DprE1) and decaprenylphosphoryl-2-keto-beta-Derythropentose reductase (DprE2).
Authors’ response: Precise details on the two isoforms of DprE1 have been added
Lines 164 and 188 contain the exact same subheading (i.e. DprE1 Covalent Inhibitors).
Authors’ response: The unnecessary subheading has been removed
Line 304: “CYP” should be spelt out as “cytochrome P450” during its initial mention.
Authors’ response: Cytochrome P450 is spelled out in the text.
Reference no. 72 is either incomplete or not supposed to be present.
Authors’ response: The incomplete reference 72 is incomplete
As other modifications have been made, the modifications are underlined in yellow in the Word version of the manuscript.
Author Response File: Author Response.pdf
Reviewer 3 Report
Comments and Suggestions for AuthorsThe review Maximilien Fil and Sandrine Alibert describes DprE1 of Mtb as a prime therapeutic target with the several inhibitors in clinical trials. The authors emphasizing the need for continued research and development in this area to address the evolving landscape of tuberculosis and drug resistance.
In the introduction it would be good to add about other known targets in anti-tuberculosis therapy.
There are only two pictures in the review! Paragraph 2.1 definitely needs the figure of arabinogalactan and scheme of arabinan synthesis with emphasizing of the pivotal role of the DprE1/DprE2 complex.
There are lots of refs after description of the each group of inhibitors. Do the authors suggest looking at the original articles? Why do I need a review then? For each group of inhibitors authors need to add figures of compounds, at least the key representatives.
Besides authors probably need to provide the summary table of best inhibitors from the each group of compounds. This will help to trace how activity changed depending on the modification of the structure.
The review of the scientific interest and can be published in BioMed after revision.
Author Response
Thank you for all comments, corrections and suggestions. They have strengthened the discussion on the challenge of developing anti-tuberculosis agents.
There are only two pictures in the review! Paragraph 2.1 definitely needs the figure of arabinogalactan and scheme of arabinan synthesis with emphasizing of the pivotal role of the DprE1/DprE2 complex.
Author response: A figure illustrating the implication of the DprE1/DprE2 complex in arabinogalactan biosynthesis has been added
There are lots of refs after description of the each group of inhibitors. Do the authors suggest looking at the original articles? Why do I need a review then? For each group of inhibitors authors need to add figures of compounds, at least the key representatives.
Autor response: A figure illustrating the key representative molecular structures of covalent and non-covalent DprE1 inhibitors has been added
Besides authors probably need to provide the summary table of best inhibitors from the each group of compounds. This will help to trace how activity changed depending on the modification of the structure.
Author response: As figures suggested by the other two reviewers have already been added, the figure illustrating the key representative molecular structures of covalent and non-covalent DprE1 inhibitors with accompanying explanations in the text is considered sufficient.
As other modifications have been made, the modifications are underlined in yellow in the Word version of the manuscript.
Author Response File: Author Response.pdf
