All reviews of published articles are made public. This includes manuscript files, peer review comments, author rebuttals and revised materials. Note: This was optional for articles submitted before 13 February 2023.
Peer reviewers are encouraged (but not required) to provide their names to the authors when submitting their peer review. If they agree to provide their name, then their personal profile page will reflect a public acknowledgment that they performed a review (even if the article is rejected). If the article is accepted, then reviewers who provided their name will be associated with the article itself.
This work underscores efflux pumps (EPs) as key drivers of multidrug resistance in bacteria, fungi, and cancer cells, while also contributing to virulence, biofilm formation, and persistence. It highlights their role in treatment failure, limitations of current detection methods, and the potential of emerging technologies like CRISPR and efflux pump inhibitors to combat resistance, despite clinical challenges.
[# PeerJ Staff Note - this decision was reviewed and approved by Valeria Souza, a PeerJ Section Editor covering this Section #]
Yes, the review is of broad and cross-disciplinary interest and fits well within the scope of the journal.
Yes, the Introduction adequately introduces the subject and clearly identifies the target audience and the motivation for the review.
Yes, the survey methodology is consistent with a comprehensive and unbiased coverage of the subject. Sources are adequately cited, with quotations and paraphrasing used appropriately. The review is logically organized into coherent paragraphs and subsections. The necessary corrections and adjustments have been made accordingly.
Yes, the argument is well developed and supported in line with the goals set out in the Introduction. The Conclusion appropriately identifies unresolved questions, gaps, and future directions. The revisions made are appropriate and address the necessary points.
Thank you for your corrections.
No comment.
No comment.
No comment.
The authors have made constructive revisions in response to the comments.
Please address the reviewers' comments.
**PeerJ Staff Note:** Please ensure that all review, editorial, and staff comments are addressed in a response letter and that any edits or clarifications mentioned in the letter are also inserted into the revised manuscript where appropriate.
This review is of broad and cross-disciplinary interest and fully aligns with the scope of the journal. This article is one of the most comprehensive review papers I have evaluated to date. Each topic related to efflux systems, ranging from microbial structures to cancer-associated mechanisms, is meticulously addressed under separate and well-organized subheadings. Furthermore, its enrichment with recent developments, clinical studies, and future perspectives enhances the article’s relevance and contribution to the field.
The structure is highly coherent, and the inclusion of chronological developments facilitates a clear understanding of both the historical context and therapeutic approaches.
Although the topic has been addressed in previous reviews, this manuscript stands out due to its comprehensive scope and depth. It integrates a wide range of aspects under distinct sections, providing a thorough and detailed synthesis that is not currently available in the recent literature. Therefore, there was a clear need for such an extensive review to consolidate existing knowledge and offer a cohesive resource for researchers across multiple disciplines.
The Introduction section effectively introduces the subject matter, clearly outlining the motivation for the review. It makes the content accessible and relevant to researchers across multiple disciplines. The background and rationale are well-articulated, providing a solid foundation for the subsequent discussions.
The survey methodology is comprehensive and well-structured, employing a PRISMA flow diagram for study selection that ensures transparent, systematic, and unbiased coverage of the subject. By including a broad range of recent and seminal studies, the review effectively captures the current state of knowledge without evident gaps or bias.
Sources are adequately cited throughout the manuscript. Relevant studies have been appropriately referenced and discussed.
The review is well-organized, with clear and coherent paragraphs and subsections that facilitate understanding and guide the reader smoothly through the topics.
The review presents a well-developed and thoroughly supported argument that aligns clearly with the goals outlined in the Introduction, effectively addressing the key topics and providing comprehensive insights.
The conclusion clearly identifies the existing challenges and unresolved issues related to efflux-mediated resistance. It also outlines potential methodologies that could be employed to address these challenges. The authors appropriately emphasize that overcoming these obstacles will require time and meticulous multidisciplinary efforts, a point with which I fully agree.
Overall, this is a comprehensive and well-structured review that addresses efflux systems in the context of antimicrobial resistance and virulence from a multidisciplinary perspective. The article is written in clear and understandable language, logically organized, and strongly supported by current literature. The inclusion of new technologies and therapeutic strategies makes the study a significant contribution to the current scientific landscape.
I commend the authors' accomplished and meticulous work.
However, I recommend further development of the discussion on future challenges and potential solutions, particularly from a clinical application perspective.
Efflux pumps are a major contributor to multidrug resistance in bacteria, fungi, and cancer cells. In this review, the authors have compiled a manuscript with the aim of comprehensively and critically summarizing the roles of efflux pumps in antibacterial and antitumor drug resistance, as well as their contributions to pathogenicity and survival, across multiple biological domains.
The review clearly organizes the evidence that multiple efflux pump families are involved in the active extrusion of antibacterial and antitumor agents, and that they mediate physiological functions such as biofilm formation, secretion of virulence factors, and metabolic adaptation, thereby emphasizing their central role in both drug resistance and pathogenicity. In addition, the authors introduce novel technological approaches while noting the limitations of classical efflux pump detection methods.
Overall, I find this to be a very well-organized and comprehensive review.
The manuscript is structured as a systematic review, summarizing its content based on the findings of previously published studies.
Rather than attempting to cover all literature exhaustively, it selectively focuses on relevant findings and presents them in a concise and well-organized manner.
As the conclusions are based on a synthesis of existing literature, they are conceptually sound.
The cross-domain summary, along with the organization of information on efflux pump inhibitors and CRISPR applications, represents a novel perspective.
The authors have provided sufficient field background and context. While the authors have maintained a professional language, there are certain ambiguities.
(i) Section 3.1, line 135, the authors mention antimicrobial compounds. If only drugs are specifically being discussed in the context of antimicrobials, then suggest this should come under the heading of efflux and antimicrobials. Otherwise, if this also includes cancer drugs, then suggest rephrasing for clarification.
(ii) Please rephrase: Lines 157-161.
(iii) Suggest categories, examples line 161 into (i) Gram-negative bacteria, (ii) Gram-positive bacteria
Rephrase 163-176:
E.g., the AcrAB-TolC system, a well-characterized RND type pump, in E. coli and Salmonella enterica, is responsible for exporting ³-lactams, tetracyclines, fluoroquinolones, and other antimicrobials (Blair et al., 2015; Nishino et al., 2021).
Please recheck punctuation marks.
The review includes new technologies used for detecting efflux and discusses limitations.
Line 427: It was identified that both synthetic and natural EIs with improved efficacy and specificity. The authors have focused on microbial cells. What about cancer treatment? Are any EIs being explored or studied for treating drug-resistant cancer/ cancer cells...any in clinical trials?
Line 549-550: irinotecan and taxanes. A phase II clinical trial (NCT04247256) is evaluating the safety, toxicity, and efficacy of combining SCO-101 with FOLFIRI. What are irinotecan, taxanes, SCO-101 & FOLFIRI?
Yes, survey methodology is consistent and comprehensive.
Regarding the methodology, it is suggested that:
The authors describe their review as narrative throughout the paper (therefore, remove systematic in the methods section of the abstract).
Please reference the supplemental figure in the methods section of the manuscript.
Conclusions are well stated. Gaps and future directions are identified.
The authors have reviewed the role of efflux pumps in the context of AMR and cancer treatment. However, there is a need to balance reporting to both. In the general sections, the examples are focused on antimicrobial agents/microorganisms.
While this is an interesting review, the authors need to highlight the role of ABC transporters in both cancer cells and bacteria, and what that means. Perhaps clarify whether common efflux inhibitors are present for both.
I would also suggest that, because there is so much information, authors try to present it in tables, and any further explanation should go in the manuscript. For instance, a table for synthetic and natural efflux inhibitors.
All text and materials provided via this peer-review history page are made available under a Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.