Round 1

Reviewer 1 Report

I really enjoyed reading this work, congratulations to authors.

I fully agree with them:

Streptomyces: still the biggest producer of new natural secondary metabolites, a current perspective

 

this is a huge scientific research field

12 document results

TITLE-ABS-KEY ( streptomyces  AND  secondary  AND  metabolite ) 

2512 documents in Scopus

 

Maybe some up to date techniques are missing in this review

genome mining etc

Complete genome analysis reveals secondary metabolite biosynthetic capabilities of Streptomyces sp. R527F isolated from the Arctic Ocean

Duan, Z., Liao, L., Chen, B.

2022

Marine Genomics 63,100949

Exploration of Diverse Secondary Metabolites From Streptomyces sp. YINM00001, Using Genome Mining and One Strain Many Compounds Approach Open Access

Liu, T., Ren, Z., Chunyu, W.-X., (...), Ding, Z.-T., Yin, M.

2022

Frontiers in Microbiology 13,831174

novelty compared to this recent publication?

 

Recently Discovered Secondary Metabolites from Streptomyces Species Open Access

Lacey, H.J., Rutledge, P.J.

2022

Molecules 27(3),887

 

 

 

 

 

 

 

 

 

 

 

 

Author Response

Dear Reviewer,

Thank you for the prompt handling of our manuscript. We appreciate the constructive comments.

As suggested, we inserted a paragraph titled “Hidden Potential of Streptomyces: Metagenomic Insights and Evidence”. A few years ago, as we entered the age of DNA sequencing and bioinformatics, the challenges were to isolate a new natural product from an uncultured and unidentified genus of bacteria that cannot be grown in the laboratory and predict the nucleotide sequence of a biosynthetic pathway. For this, the screening of metagenomic data has revealed a huge hidden potential in bacteria. Today, in the post-genomic era, the challenge is to activate these cryptic gene clusters in the laboratory, capable of coding for a plethora of previously undetected complex secondary metabolites. For the latter, various strategies have been developed to activate cryptic gene clusters in microorganisms that may lead to the identification of novel yet unidentified secondary metabolites for therapeutic and other use. Our review presents two of the strategies or directions that researchers are taking these days, namely: Bioprospecting in extremely unusual environments and expanding knowledge of culture-based techniques. So, the purpose of putting the paragraph on metagenomics after the introduction is to let readers know that culture-independent methods has shown the immense potential of this genus, and now the trick is to have a holistic perspective on various environments and methods and design isolation methods accordingly.

Also, our co-author Prof. Robert Keyzers has proofread our manuscript for English revisions as suggested.

Yours sincerely,

Atanas Pipite

Reviewer 2 Report

The manuscript “Streptomyces: still the biggest producer of new natural secondary metabolites, a current perspective” by L. Donald et al. is a review focused on the isolation of new streptomycetes with biologically active secondary metabolites. The review covers years 2015-2020 and somewhat systematizes the data by isolation source, bioactivity and structure of the active compounds.

The text is hard to read, poorly formatted and often contains repetitions. The manuscript could probably be reconsidered only after major revision and intensive rewriting.

Metagenomic and genome mining approaches to the discovery of new bioactive natural products deserve some discussion because discovered BGCs and similar genes are found in Streptomyces genomes [10.1021/jacs.8b12087], [10.1038/s41564-018-0110-1], [10.1039/D0NP00071J] [10.1016/j.csbj.2020.06.024], [10.1126/sciadv.aay5781]. Thus, isolation of new natural secondary metabolites of interest is not always accompanied by the discovery and of new Streptomyces strains [10.1039/d0np00089b] [10.1021/acs.jnatprod.0c00152], [10.1016/j.csbj.2021.02.017], [10.1002/anie.202104528], [10.1038/s41429-020-0304-7], [10.1039/c8ob03115k], [10.1038/s41467-019-08438-0], [10.1016/j.tet.2018.11.015], [10.1021/acs.orglett.7b01807], [10.1038/ja.2015.121], etc. These and similar cases should be mentioned.

Some revisions needed are marked below:

line 4: corresponding authors should be marked;

line 17: There – don’t use bold font;

lines 37-38: Please, rewrite and remove the repetitions (increase… increases);

lines 41-42: ref.3 – It’s a short comment about phytochemicals, that’s not relevant;

lines 49-50: Please, rewrite and remove the repetitions (decrease… decrease);

lines 52-54: Please, rewrite the sentence (“Therefore, ….”) for clarity;

lines 75-78: Please, rewrite and remove the repetitions (great… great… greatest…);

line 77: “To date, Streptomycetes still produce the greatest number of natural products compared to other genera of Actinobacteria and there is a growing trend for the discovery of new Streptomyces species” – That’s a strange conclusion. The fact is the streptomycetes are the most frequently isolated species among actinobacteria. Consequently the compounds from this source are much more studied, that’s not a “trend”.

line 80: incorrect reference “Laskariset al. (2021)”;

line 82:  streptomyces – Streptomyces;

line 85: the dot at the next line;

line 94: “with insects, and living in symbiosis with plants, fungi, and other animals” – fungi are not animals. Please, rewrite for clarity;

lines 109-113: the sentences repeat the previous text (see lines 99-102);

p.4, ref.28: Please, remove the text “which had been filter sterilized (0.22 ?m pore) before being added to 45℃ molten”;

page 9, ref.86: the “-“ in the first column should be removed;

tables 4&5: Streptomyces should be italicized;

line 253: Streptomycetes spp. - Streptomyces spp.;

p.25, ref.164:  the “-“ in the second column should be removed;

figs. 1-4: Please, remove the grey background and make the legend more readable (increase the font size and use bold font);

table 9: Better use “G+” and “G-“ for bacteria;

table 10: ref. 253 “Phenazin”, ref.256 “Lasso peptide”, ref.263 ”Cyclohexenone-containing linear polyketide” are darkened.

fig. 6: chemical structures have different sizes;

table 12: Please, format the table: the line numbers should be outside;

p. 41: beginning with line 295, the text is not formatted in the same style;

Fig. 10: Please, move the caption of the figure to the same page;

line 354: The heading “Appendix” should be formatted in the same style.

Author Response

Dear Reviewer,

Thank you for the prompt handling of our manuscript. We appreciate the constructive comments and we think the suggested addition will result in a manuscript of greater interest to your readers. Below we have indicated how we have modified our existing manuscript.

First, as suggested, we inserted a paragraph titled “ Hidden Potential of Streptomyces: Metagenomic Insights and Evidence”. A few years ago, as we entered the age of DNA sequencing and bioinformatics, the challenges were to isolate a new natural product from an uncultured and unidentified genus of bacteria that cannot be grown in the laboratory and predict the nucleotide sequence of a biosynthetic pathway. For this, the screening of metagenomic data has revealed a huge hidden potential in bacteria. Today, in the post-genomic era, the challenge is to activate these cryptic gene clusters in the laboratory, capable of coding for a plethora of previously undetected complex secondary metabolites. For the latter, various strategies have been developed to activate cryptic gene clusters in microorganisms that may lead to the identification of novel yet unidentified secondary metabolites for therapeutic and other use. Our review presents two of the strategies or directions that researchers are taking these days, namely: Bioprospecting in extremely unusual environments and expanding knowledge of culture-based techniques. So, the purpose of putting the paragraph on metagenomics after the introduction is to let readers know that culture-independent methods has shown the immense potential of this genus, and now the trick is to have a holistic perspective on various environments and methods and design isolation methods accordingly.

Second, we made the minor edits suggested below and checked our references for consistency.

Point 1. line 4: corresponding authors should be marked;

Response: Corresponding author “Atanas Pipite” was marked with an asterisk (*) in the authors list

Point 2. line 17: There – don’t use bold font;

Response : the bold font was removed from “There”

Point 3. lines 37-38: Please, rewrite and remove the repetitions (increase… increases);

Response: the word ‘increase’ was replace by the words ‘rise’ in line 37

Point 4. lines 41-42: ref.3 – It’s a short comment about phytochemicals, that’s not relevant;

Response: Lines 41-42 including the reference was deleted

Point 5. lines 49-50: Please, rewrite and remove the repetitions (decrease… decrease);

Response: the word ‘decline’ was used to replace the word decrease in line 49

Point 6. lines 52-54: Please, rewrite the sentence (“Therefore, ….”) for clarity;

Response: Sentence re-written to ‘Therefore the need to produce new antibiotics has driven researchers to put more effort into finding new and novel natural products from untouched and underexplored habitats’

Point 7. lines 76-79: Please, rewrite and remove the repetitions (great… great… greatest…);

Response: These words were replaced by ‘highest’ and ‘significant’ respectively

Point 8. line 80: “To date, Streptomycetes still produce the greatest number of natural products compared to other genera of Actinobacteria and there is a growing trend for the discovery of new Streptomyces species” – That’s a strange conclusion. The fact is the streptomycetes are the most frequently isolated species among actinobacteria. Consequently, the compounds from this source are much more studied, that’s not a “trend”.

Response: Sentence corrected to ‘Since the isolation techniques of Streptomycetes are well understood, this genus has been frequently isolated. Consequently, Streptomyces genus produces the highest number of natural products compared to other genera of Actinobacteria'.

Point 9. line 80: incorrect reference “Laskariset al. (2021)”;

Response: The citation Laskaris et al (2021) was not removed but a proper reference was inserted as [18] at the end of the sentence

Point 10. line 82:  streptomyces – Streptomyces;

Response: Streptomyces in lines 82 has been changed to ‘Streptomycetes’

Point 11. line 85: the dot at the next line;

Response: Dot was placed next to the word ‘compound’

Point 12. line 94: “with insects, and living in symbiosis with plants, fungi, and other animals” – fungi are not animals. Please, rewrite for clarity;

Response: The word “other” was deleted from this sentence  

Point 13. lines 109-113: the sentences repeat the previous text (see lines 99-102);

Response: Lines 99-102 were omitted

Point 14. p.4, ref.28: Please, remove the text “which had been filter sterilized (0.22 ?m pore) before being added to 45℃ molten”;

Response: The text was deleted

Point 15. page 9, ref.86: the “-“ in the first column should be removed;

Response: The “-“ from the first column was removed

Point 16. tables 4&5: Streptomyces should be italicized;

Response: Streptomyces in table 4 ref.144 have been italicized

Point 17. line 253: Streptomycetes spp. - Streptomyces spp.;

Response: Streptomycetes spp. was changed to Streptomyces spp.

Point 18. p.25, ref.164:  the “-“ in the second column should be removed;

Response: The “-“ from the second column was removed

Point 19. figs. 1-4: Please, remove the grey background and make the legend more readable (increase the font size and use bold font); -

Response: Grey background was removed from figs. 1-4 and legend was changed to font size 10, bold font

Point 20. table 9: Better use “G+” and “G-“for bacteria;

Response: G+ve and G-ve was changed to G+ and G- in table 9.

Point 22. table 10: ref. 253 “Phenazin”, ref.256 “Lasso peptide”, ref.263” Cyclohexenone-containing linear polyketide” are darkened.

Response: The mentioned chemical classes were deleted and written without a darkened background

Point 23. fig. 6: chemical structures have different sizes;

Response: All structures in fig. 6 were resized

Point 24. table 12: Please, format the table: the line numbers should be outside;

Response: Table 12 was formatted accordingly.

Point 25. p. 41: beginning with line 295, the text is not formatted in the same style;

Response: The text and the title was formatted to the same style as the other texts

Point 26. Fig. 10: Please, move the caption of the figure to the same page;

Response: Fig. 10 was resized so that the caption placed on the same page

Point 27. line 354: The heading “Appendix” should be formatted in the same style.

Response: The heading was formatted to font size 14, Arial font

Lastly, our co-author Prof. Robert Keyzers has proofread our manuscript for English revisons as suggested.

Atanas Pipite

Round 2

Reviewer 2 Report

In present form the manuscript is suitable for publication, however, the reference list should be carefully checked upon production.