Complexation of Terpenes for the Production of New Antimicrobial and Antibiofilm Molecules and Their Encapsulation in Order to Improve Their Activities

Round 1

Reviewer 1 Report

This review article discussed the development of novel antimicrobial complexes derived from terpenes and efforts in improving their bioactivities and characteristics by using a formulation based on microencapsulation. Generally, the manuscript is well reviewed and the topic is interesting. I would like to recommend its publication after some minor revisions, especially for literature balance.

Major

1. Section 4.1 should be expanded by discussing how biofilm formation was regulated by small molecules because this can generate more antibiofilm strategies, such as Liu et al. 2022, Biofilm control by interfering with c-di-GMP metabolism and signaling, Biotechnology Advances, DOI: 10.1016/j.biotechadv.2022.107915

2. At the end of this paper, the authors should provide one section to discuss what are the pespectives of this field.

Minor

1. L15, the most important issues

2. L16, adherent cells

3. L34-36, provide an example to explain this issue, such as biofouling issues by Sousa et al. 2023, J. Mater. Chem. B, DOI: 10.1039/D3TB00704A.

3. L122-133, please discuss this case using some examples, such as Liu et al. 2014, MethodsX, DOI: 10.1016/j.mex.2014.08.008

4. L164-166, add the reference by Flemming, HC., Wingender, J. The biofilm matrix. Nat Rev Microbiol 8, 623–633 (2010).

Author Response

First of all, we would like to thank you for your efforts and your comments.

      Major

1. As instructed Section 4.1 is completed by a discussion of how biofilm formation was regulated by small molecules. (L 189-197).
2. As requested, at the end of this document, a section has been added to discuss the perspectives in this field. (L465-473).

Minor

1. You asked me to provide an example to explain this issue (L34-36), but The article published by Sousa and al. reported that cholesterol-modified DNA micelles and stabilized with polymyxin B present antibacterial and antibiofilm potentials. The incorporation of polymyxin B into the DNA micelles showed the formation of micellar structures with greater control over size distributions and enhanced resistance to serial dilutions in comparison to plain ssDNA micelles. These findings are not consistent with the idea developed in the introduction section L40-42.
2. As requested, examples of new strategies based hurdle technology, using safe biochemical agents that show effective antibiofilm activities are added (L146-152).
3. As requested, the reference Flemming, HC., Wingender, J. The biofilm matrix. Nat Rev Microbiol 8, 623-633 (2010) is added (see L212 ).

Reviewer 2 Report

 This review paper is well written. I recommend accepting it after a minor revision. There are a few cases where it can be upgraded. Here I am suggesting some upgrades:

·       Rewrite the abstract. Your abstract should have all the main information you found in reviewing it.

·       introduction: add more recent studies. explain the goal of this review in a better way.

·       Section 2: Explain more about healthcare-associated infections (HAIs) with more recent references.

·       Explain Fig. 1 in a better way.

·       define EPS at first, where you are writing it.

·       The structure of Borneol has a red font. Explain the reason. otherwise correct it.

·       line number 250-252: correct the sentence construction.

·       Figure 5: The resolution is poor. Correct it with a better resolution figure.

·       mention the correct format and font in Table 6.

·       Explain Figure 6 (a schematic representation of the spray-drying microencapsulation process) in the text. Otherwise, it makes no sense.

·       The conclusion is too long. Rewrite it and summarize it.

Comments for author File: Comments.pdf

Author Response

First of all, we would like to thank you for your efforts and your comments.

• The abstract is rewritten as requested (L16-31)
• In the introduction as you requested, the objective is explained more precisely (L88-93).
• In section 2, more details were given to explain healthcare-associated infections (HAIs) 2023 (L101-109). Most of the references in this paragraph are between 2017 and 2023.
• As requested, Figure 1 is explained in detail (L168-178).
• The PSE definition is shown in the line (L169-171).
• I corrected Borneol's structure (black font).
• As you requested: the construction of the sentence on (L 293-295) has been revised.
• The figure is replaced by a new, clearer one explaining the same concept.
• In accordance with your request, the format and font are rectified in Table 6
• As requested Figure 6 is explained in (L410-418).
• The conclusion is summarized as you asked ,(L453-463).

Reviewer 3 Report

The review article authored by Y. El Fannassi et al. is devoted to an extremely important problem of the search for novel biosourced compounds with antimicrobial activity, low toxicity and low cost. The authors have chosen terpene-derived metal complexes as target compounds for discussion. However, it should be noted that the discussion of these complexes starts only on p. 13. Before that the authors provide discussions on healthcare-associated infections and food poisoning related to adherent bacteria and their biofilms, describe the nature of biofilms and discuss the antimicrobial and antibiofilm activity of different terpenes. All these issues are also important but, in my opinion, the main subjects of the discussion in this Review titled “Complexation of terpenes for the production of new antimicrobial and antibiofilm molecules and their encapsulation in order to improve their activities” are metal complexes based on terpene ligands, and they should be given more space, while the accompanying descriptive material could be shortened. Also, all the references should be formatted according to the Instructions for Authors provided on the website of the journal and avoiding French words. In general, the Review is well-organized, well-written and rather comprehensive. I can recommend publishing it in “Applied Sciences” after some minor points raised above will be addressed.

The manuscript contains some minor errors, which can be detected and corrected with the help of free online editing services like Wordtune or Writefull.

Author Response

First of all, we would like to thank you for your efforts and your comments. We completely agree with your opinion, but the purpose of this review is to highlight the potential use of terpene ligands to create new antibacterials and antibiofilms by organic synthesis. As well as highlighting the microbial risks associated with biofilms,in addition the importance of formulation based on encapsulation by using spray drying.We think, therefore, that the increase in the complexation section will profoundly modify the objectives of the review, however we are working on a review focusing only on complexes which will be submitted next Month.

Thank you for your advices.

Reviewer 4 Report

This manuscript by Fannassi et al. reviewed the terpenes for the production of antimicrobial and antibiofilm molecules. This manuscript also reviewed how to improve bioactivity by using microencapsulation. This manuscript fits the scope of Applied Sciences journal, and it can be accepted as the present form.  

    As a review manuscript, the topics to discuss terpenes as antibiofilm compounds and encapsulation of terpenes for better bioactivities. The methodology for reviewing these topics included the discussion about adherent bacteria and their biofilms. The review for these subtopics is well organized. Controls may not need for the review, summarization and discussion for these topics. A specific improvement can be for section 4.1 Biofilm matrix. The EPS was discussed in this section, and some more information about the current methods to inhibit the EPS formation can be added. The mechanisms about EPS regulation and inhibition strategies can also be discussed.  

    The conclusions of this review manuscript are consistent with the evidence and arguments discussed in the manuscript and they address the main topics discussed. The future research directions and perspectives can be added to provide a more informative conclusion section in this manuscript.

Author Response

First of all, we would like to thank you for your efforts and your comments.

• As you requested, section 4.1 is improved by a detailed description of biofilm formation, a definition of EPS, resistance caused by the QS system, and some inhibition methods ( L168-197).
• As requested, at the end of this document, a section has been added to discuss the perspectives in this field. (L465-473).

Reviewer 5 Report

Dear Authors

I read the review paper and happily endorsed the publication of this manuscript in present form.

Author Response

We would like to thank you for your efforts and your comments.