Bioactive Diepoxy Metabolites and Highly Oxygenated Triterpenoids from Marine and Plant-Derived Bacteria and Fungi

Round 1

Reviewer 1 Report

Dear Editor,

I read with great interest the article "Bioactive Secondary Metabolites of Microbial Symbionts" presented in Microbiology Research (Manuscript ID: microbiolres-2776563).

The article is devoted to oxidized secondary metabolites, which are produced by symbiotic bacteria, pathogenic fungi, or fungal endophytes, as well as some other organisms. The article presents two groups of natural metabolites such as diepoxides and highly oxygenated triterpenoids. For each group, literature data on their biological activity is provided. The first group, which includes diepoxides, is very rarely covered in the scientific literature, so the data presented are undoubtedly of interest from the point of view of pharmacology and medicine, since they are potential anticancer agents.

The second group of natural metabolites includes highly oxygenated triterpenoids, secosteroids, ergostane-type steroids, and meroterpenoids from various marine and plant-derived fungi. This group is interesting because some of its members demonstrate anti-inflammatory, antibacterial, antifungal, antiviral, and cytotoxic effects.

Both groups of secondary metabolites are provided with interesting 3D pictures of biological activities for each group of compounds. In general, the article is of great interest for academic science and for pharmaceutical companies as potential drugs for the treatment or prevention of various diseases.

The article is written in good English and provided with sufficient quantitative literature sources.
Without taking into account minor typos, the article can be accepted for publication in Microbiology Research and sent for publication in its current form.

Comments for author File: Comments.pdf

Author Response

Reviewer 1

The author is grateful to Reviewer 1 for the critical comments made to the presented review.

Thanks to you, we have supplemented the article with some additions, which are highlighted in blue, and also made corrections to found inaccuracies.

Thank you for recommending this article for publication in Microbiology Research.

Author Response File: Author Response.pdf

Reviewer 2 Report

The article explores diverse bioactive compounds from microbial symbionts, showcasing metabolites such as diepoxides and triterpenoids from marine and terrestrial microorganisms. It highlights their potential therapeutic applications, emphasizing the importance of microbial natural products in drug discovery. The manuscript has some inconsistencies that need to be addressed.

In Line 73, a paragraph begins describing fungal endophytes in hosts as producers of relevant metabolites. The author proceeds with diepoxides from fungi but also includes diepoxides from bacteria like Pseudomonas (Line 82) and Streptomyces (Line 101). Line 118 tables the biological activities of diepoxides produced by fungi and fungal endophytes. It's unclear if this refers to bacterial and fungal endophytes. The author should clarify if they are discussing fungi and bacterial metabolites.

 There is also a misunderstanding regarding the use of ‘fungal endophytes and fungi’ (mentioned again in line 335). Within the scope of this manuscript, fungal endophytes and fungi are all fungal symbionts and hence can be replaced. Otherwise, fungi should be explicitly defined.

 In Table 1, 'Pa' and 'Pa*' should be defined, as they are not standard names for predicted activity. The author should briefly discuss how activity prediction and calculation were achieved. Pa definition in all tables

 The review is about microbial symbionts but author described many compounds from algae, sponges and corals etc without specifying the microbe responsible for the production of the compounds. While it is established that microbial symbionts produced many compounds which were initially attributed to the host organism, hosts also produces some metabolites. To enhance clarity, it would be beneficial for the author to specify the microbial symbionts associated with the compounds mentioned in the review from algae, sponge, coral sources etc.

 Table 2 ‘Biological activities of diepoxides produced by marine fungi and fungal endophytes’. Only compounds from the host macroorganisms are discussed. It is unclear if all compounds are from the fungal symbionts. The author should specify the microbial origin if the focus is on microbial symbionts.

Lines 316 and 317 should include bacteria, and terms should be consistent, either 'oxygenated triterpenoids' or 'secosteroids.'

Regarding the difference between (3) Highly oxygenated triterpenoids derived from microbial symbionts' and '(4) Highly oxygenated triterpenoids derived from marine bacterial species and fungal endophytes,' the source is the distinguishing factor, as microbial symbionts include marine endophytes. The title of (3) should be modified to include 'terrestrial.'

 In Line 405, for consistency, the title should employ 'oxygenated triterpenoids' instead of 'secosteroids.' It also refers to bacteria and fungi, not just bacteria. All tables and figure legends in this manuscript should be carefully revised to reflect the descriptions in the various paragraphs.

 In Line 468, 'Corticosteroids are similar to eczema' should be corrected to 'Psoriasis is similar to eczema.'

 Minor inconsistencies in the bibliography have been noted, such as capitalizing the first letters after colons (:) in some references."

Author Response

Reviewer 2

The author is grateful to reviewer 2 for his detailed review of the article.

Below is information about the changes and additions that were made to the article.

All recommended comments have been eliminated on lines 82, 101, 118, 316, 317, 335, 405, and 468 or added to and highlighted in blue. With regard to Table 1 and other Tables and the recommendation to define “Pa” and “Pa*”, since they are not standard names for predicted activity, the data was taken from the referenced articles. Since we did not calculate "Pa", the explanation can be found in previously published articles.

Regarding the comment that microbial symbionts are not indicated for some species of algae, sponges, or corals, then upon careful reading, we point out that the symbionts are not indicated because they were not isolated, however, possible names of the symbionts are given or links are given to the relevant articles.

The names of the Tables have been corrected or clarified, and the subheadings have been corrected.

I will be glad if my explanations were comprehensive and useful.

Author Response File: Author Response.pdf

Reviewer 3 Report

The article "Bioactive Secondary Metabolites of Microbial Symbionts" by Valery M. Dembitsky explores the range of biologically active compounds derived from microbial symbionts. It particularly focuses on the isolation and characterization of diepoxides, highly oxygenated triterpenoids, secosteroids, ergostane-type steroids, and meroterpenoids from various marine and plant-derived fungi. The paper discusses the potential of microbial symbionts as a rich source of novel bioactive compounds with diverse therapeutic applications, emphasizing the importance of marine and fungal biodiversity in drug discovery and development​​. However, there are structural aspects that could be improved for better clarity and impact.

1. While the paper covers a range of topics related to microbial symbionts and their metabolites, the organization of these topics could be improved. A more structured flow that methodically progresses from general concepts to specific examples would enhance readability and understanding. For instance, introducing the broader context of microbial symbionts and their ecological roles could precede the detailed exploration of specific compounds and their applications.

2. The sections on different types of compounds (e.g., diepoxides, oxygenated triterpenoids, secosteroids) could benefit from clearer distinctions and transitions. Introducing each section with a brief overview of its significance in the broader context of microbial symbionts and bioactive compounds would help readers understand the relevance of each section in the overall narrative of the paper.

3. The author is trying to talk about bioactive secondary metabolites from microbial symbionts in the paper, however it particularly focuses on diepoxides and highly oxygenated triterpenoids, what about other kinds of compounds, e.g.  alkaloids, peptides.

Author Response

Reviewer 3

The author is grateful to Reviewer 3 for the critical comments made regarding the presented review.

Thanks to you, we have updated the article with some additions, which are highlighted in blue.

The article provides a full explanation of what Diepoxy compounds or Highly Oxygenated Triterpenoids are and both groups are characterized by both biological activities, in particular, anti-cancer activity.

In addition, for the most interesting from a pharmacological point of view, 3D graphs are provided that demonstrate the dominant activities.

I would like to hope that my additions and changes improved the article.

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

The manuscript is suitable for publication now.