Synergistic combination of two antimicrobial agents closing each other's mutant selection windows to prevent antimicrobial resistance.
Synergistic combination of two antimicrobial agents closing each other's mutant selection windows to prevent antimicrobial resistance.
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两种抗菌药物的协同组合关闭彼此的突变选择窗口以防止抗菌药物耐药性
DOI：
10.1038/s41598-018-25714-z
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发表时间：
2018-05-08
影响因子：
4.6
通讯作者：
Zhou M
中科院分区：
文献类型：
--
作者：
Xu X;Xu L;Yuan G;Wang Y;Qu Y;Zhou M
抗菌素耐药性严重威胁人类健康。联合治疗通常是对抗耐药性的有效策略，但关于其效果的一些数据是相互矛盾的。为探讨其原因，采用棋盘法测定三种设计组合对耐甲氧西林金黄色葡萄球菌（MRSA）的分数抑制浓度指数（FICIs），并首先采用琼脂平板测定其单独或不同比例组合抑制菌落形成的最低浓度（mic99%）和突变预防浓度（MPCs）。结果表明，不同比例的组合具有不同的MPCs和突变体选择窗口（MSWs），并且两种组合中的fici越小，它们的MSWs越有可能相互关闭。由于联合用药两种药物的药代动力学特性不同，即使按一定比例给药，两种药物在血液和感染部位的比例也可能不同，从而导致预防耐药的效果不同。因此，这些实验结果从理论上表明，根据MSW和MPC的假设，相互封闭的MSW协同组合具有很大的耐药效力，并推断出组合的体内协同有效性可能是预防耐药的关键。罗红霉素/强力霉素对MRSA 01和MRSA 02的fici分别为0.26 ~ 0.50和0.28 ~ 0.38，两者的msw可以在一定比例范围内同时关闭，但对其他药物无效。同时，其防耐药效果有待进一步验证。
Antimicrobial resistance seriously threatened human health. Combination therapy is generally an effective strategy to fight resistance, while some data on its effects are conflicting. To explore the reasons, the fractional inhibitory concentration indexes (FICIs) of three designed combinations against methicillin-resistant Staphylococcus aureus (MRSA) were determined using checkerboard method, and their minimal concentrations inhibiting colony formation by 99% (MIC99%s) and mutant prevention concentrations (MPCs) alone or in combinations including different proportions were first determined using agar plates. The results indicated that different proportions of a combination had presented different MPCs and mutant selection window (MSWs), and also showed that the smaller the FICIs of two agents in combinations were, the more probable their MSWs were to close each other. As two agents of a combination had different pharmacokinetic characters, the ratios of two agents in blood and infectious sites were likely different even though a specific proportion was administrated, which would lead to different effects preventing resistance. Thereby, these experimental results theoretically indicated that synergistic combination closing each other’s MSWs had a great potency to prevent resistance according to the hypotheses of MSW and MPC, and deduced that in vivo synergistic validity of a combination was likely a key to prevent resistance. Moreover, a synergistic combination of roxithromycin/doxycycline with the FICIs of 0.26–0.50 and 0.28–0.38 respectively against MRSA 01 and 02 was obtained, and the MSWs of these two agents could be simultaneously closed each other in a certain range of proportions, but for others. Meanwhile, its effect preventing resistance needs to be further verified.
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影响因子：
5.4
作者：
Fischbach, Michael A.
通讯作者：
Fischbach, Michael A.
DOI：
10.1126/science.aad3292
发表时间：
2016-01-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Baym M;Stone LK;Kishony R
通讯作者：
Kishony R
影响因子：
4.9
作者：
Robertson, Gregory T.;Bonventre, Eric J.;Lynch, A. Simon
通讯作者：
Lynch, A. Simon
影响因子：
4.9
作者：
Sindelar, G;Zhao, XL;Drlica, K
通讯作者：
Drlica, K
影响因子：
11.8
作者：
Boucher, Helen W.;Talbot, George H.;Bartlett, John
通讯作者：
Bartlett, John