PreprintArticleVersion 2Preserved in Portico This version is not peer-reviewed
Drug Combinations to Prevent Antimicrobial Resistance: Some Correlations and Laws, and their Verifications, thus Proposing Some Principles and a Preliminary Scheme
Version 1
: Received: 6 August 2022 / Approved: 9 August 2022 / Online: 9 August 2022 (04:19:53 CEST)
Version 2
: Received: 13 September 2022 / Approved: 13 September 2022 / Online: 13 September 2022 (07:53:32 CEST)
Yi, H.; Yuan, G.; Li, S.; Xu, X.; Guan, Y.; Zhang, L.; Yan, Y. Drug Combinations to Prevent Antimicrobial Resistance: Various Correlations and Laws, and Their Verifications, Thus Proposing Some Principles and a Preliminary Scheme. Antibiotics, 2022, 11, 1279. https://doi.org/10.3390/antibiotics11101279.
Yi, H.; Yuan, G.; Li, S.; Xu, X.; Guan, Y.; Zhang, L.; Yan, Y. Drug Combinations to Prevent Antimicrobial Resistance: Various Correlations and Laws, and Their Verifications, Thus Proposing Some Principles and a Preliminary Scheme. Antibiotics, 2022, 11, 1279. https://doi.org/10.3390/antibiotics11101279.
Yi, H.; Yuan, G.; Li, S.; Xu, X.; Guan, Y.; Zhang, L.; Yan, Y. Drug Combinations to Prevent Antimicrobial Resistance: Various Correlations and Laws, and Their Verifications, Thus Proposing Some Principles and a Preliminary Scheme. Antibiotics, 2022, 11, 1279. https://doi.org/10.3390/antibiotics11101279.
Yi, H.; Yuan, G.; Li, S.; Xu, X.; Guan, Y.; Zhang, L.; Yan, Y. Drug Combinations to Prevent Antimicrobial Resistance: Various Correlations and Laws, and Their Verifications, Thus Proposing Some Principles and a Preliminary Scheme. Antibiotics, 2022, 11, 1279. https://doi.org/10.3390/antibiotics11101279.
Abstract
Antimicrobial resistance (AMR) has been a serious threat to human health, and combination therapy is proved to be an economic and effective strategy to fight the resistance. However, the abuse of drug combinations would conversely accelerate the spread of AMR. In our previous work, it had been concluded that the mutant selection indexes (SIs) of one agent against a specific bacterial strain are closely related to the proportions of two agents in a drug combination. To discover probable correlations, predictors and laws for further proposing feasible principles and schemes guiding the AMR-preventing practice, here three aspects were further explored. First, the power function (y=axb, a > 0) correlation between the SI (y) of one agent and the ratio value (x) of two agents in a drug combination was further established based on the mathematical and statistical analyses for those experimental data, and two rules a1 × MIC1 = a2 × MIC2 and b1 + b2 = -1 were discovered from both equations of y=a1xb1 and y=a2xb2 respectively for two agents in drug combinations. Simultaneously, it was found that one agent with larger MPC alone for drug combinations show greater potency for narrowing itself MSW and preventing the resistance. Second, a new concept as mutation-preventing selection index (MPSI) was proposed and used for evaluating the mutation-preventing potency difference of two agents in drug combinations, and the positive correlation between the MPSI and the mutant prevention concentration (MPC) or minimal inhibitory concentration (MIC) was subsequently established. Inspired by this, the significantly positive correlation, contrary to previous reports, between the MIC and the corresponding MPC of antimicrobial agents against pathogenic bacteria was established using one hundred and eighty-one of data pairs reported. These results together of above three aspects indicate that the MPCs in alone and combination are very important indexes for drug combinations to predict the mutation-preventing effects and the trajectories of collateral sensitivity, and while the MPC of an agent can be roughly calculated from its corresponding MIC. Subsequently, the former conclusion was further verified and improved by the antibiotic exposure to forty-three groups designed as different drug concentrations and various proportions. The results further proposed that the C/MPC for the agent with larger proportion in drug combinations can be considered as a predictor and is the key to judge whether the resistance and the collateral sensitivity occur to two agents. Based on these above correlations, laws, and their verification experiments, some principles were proposed, and a diagram of the mutation-preventing effects and the resistant trajectories for drug combinations with different concentrations and ratios of two agents was presented. Simultaneously, the reciprocal of MPC alone (1/MPC), proposed as the stress factors of two agents in drug combinations, together with their SI in combination, is the key to predict the mutation-preventing potency and control the trajectories of collateral sensitivity. Finally, a preliminary scheme for antimicrobial combinations preventing the AMR was further proposed for subsequent improvement research and clinic popularization, based on the above analyses and discussion. Moreover, some similar conclusions were speculated for triple or multiple drug combinations.
Medicine and Pharmacology, Pharmacology and Toxicology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received:
13 September 2022
Commenter:
Ganjun Yuan
Commenter's Conflict of Interests:
Author
Comment:
Dear Editor,
According to the suggestions raised from several reviewers, my co-authors and I have amended the manuscript, and have pleasure to submit the revised version, for your consideration.
Many thanks for your kind attention!
Yours sincerely,
Ganjun Yuan
Here are our detailed revisions. On the whole, we had carefully revised throughout the original manuscript, including sections Abstract, Introduction, Results, Discussions, Methods, References, and Abstract graphic. 1. Main revisions for section Abstract The logic of section Abstract had been improved, and some texts and expressions were revised. Furthermore, some text was deleted for highlighting the key points. 2. Main revisions for section Introduction To increase the logic and sufficiently present the background, we had performed extensive revisions for paragraph 1, 3 and 4. 3. Main revisions for section Results We had revised the expression in the introductory sentence of each subsection, and adjusted Table 3 as Tables 3 and S5 in the revised manuscript. Moreover, a large amount of revisions had been performed for the expression of subsection 2.2. 4. Main revisions for section Discussions Figure 3 had been revised for clearly presenting the logic of this research. Moreover, some expressions were also revised for increasing the logic of this section. 5. Main revisions for section Methods To improve the logic of this section corresponding to section 2. Results, we had adjusted the arrangement of subsection, and moved subsection 4.3 to subsection 4.1, and respectively revised subsections 4.1, 4.2, 4.4 and 4.5 as subsections 4.2.1, 4.2.2, 4.2.3 and 4.2.4 of section 4.2. Moreover, we had provided more detailed information for repeating this research. 6. Main revisions for section References We had inserted another two references and deleted one reference. As many revisions were performed for the manuscript, we had carefully the references, and revised their numbers. 7. Revisions for Abstract graphic Depending on the revision for Figure 3, we had revised Abstract graphic for clearly presenting the logic of this research.
Commenter: Ganjun Yuan
Commenter's Conflict of Interests: Author
According to the suggestions raised from several reviewers, my co-authors and I have amended the manuscript, and have pleasure to submit the revised version, for your consideration.
Many thanks for your kind attention!
Yours sincerely,
Ganjun Yuan
Here are our detailed revisions.
On the whole, we had carefully revised throughout the original manuscript, including sections Abstract, Introduction, Results, Discussions, Methods, References, and Abstract graphic.
1. Main revisions for section Abstract
The logic of section Abstract had been improved, and some texts and expressions were revised. Furthermore, some text was deleted for highlighting the key points.
2. Main revisions for section Introduction
To increase the logic and sufficiently present the background, we had performed extensive revisions for paragraph 1, 3 and 4.
3. Main revisions for section Results
We had revised the expression in the introductory sentence of each subsection, and adjusted Table 3 as Tables 3 and S5 in the revised manuscript. Moreover, a large amount of revisions had been performed for the expression of subsection 2.2.
4. Main revisions for section Discussions
Figure 3 had been revised for clearly presenting the logic of this research. Moreover, some expressions were also revised for increasing the logic of this section.
5. Main revisions for section Methods
To improve the logic of this section corresponding to section 2. Results, we had adjusted the arrangement of subsection, and moved subsection 4.3 to subsection 4.1, and respectively revised subsections 4.1, 4.2, 4.4 and 4.5 as subsections 4.2.1, 4.2.2, 4.2.3 and 4.2.4 of section 4.2. Moreover, we had provided more detailed information for repeating this research.
6. Main revisions for section References
We had inserted another two references and deleted one reference. As many revisions were performed for the manuscript, we had carefully the references, and revised their numbers.
7. Revisions for Abstract graphic
Depending on the revision for Figure 3, we had revised Abstract graphic for clearly presenting the logic of this research.