Departamento de Genética, Fisiología y Microbiología, Universidad Complutense, Madrid, Spain.
Unidad de Genética Bacteriana, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain.
Antimicrob Agents Chemother. 2019 Jul 25;63(8). doi: 10.1128/AAC.00737-19. Print 2019 Aug.
We studied the molecular mechanisms involved in the postantibiotic effect of the fluoroquinolones levofloxacin and moxifloxacin in Wild-type strain R6 had postantibiotic effects of 2.05 ± 0.10 h (mean ± standard deviation [SD]) and 3.23 ± 0.45 h at 2.5× and 10× MIC of levofloxacin, respectively. Moxifloxacin exhibited lower effects of 0.87 ± 0.1 and 2.41 ± 0.29 h at 2.5× and 10× MIC, respectively. Fluoroquinolone-induced chromosome fragmentation was measured at equivalent postantibiotic effects for levofloxacin (2.5× MIC) and moxifloxacin (10× MIC). After 2 h of drug removal, reductions were approximately 7-fold for levofloxacin and 3-fold for moxifloxacin, without further decreases at later times. Variations in reactive oxygen species production were detected after 4 to 6 h of drug withdrawals, with decreases ≥400-fold for levofloxacin and ≥800-fold for moxifloxacin at 6 h. In accordance, after 4 to 6 h of drug withdrawal, the levofloxacin-induced upregulation of the operon, introducing iron in the bacteria, decreased up to 2- to 3-fold, and the moxifloxacin-induced upregulation of several genes involved in the production of pyruvate was reduced 3- to 7-fold. In accordance, lower postantibiotic effects (up to 1 h) were observed in strain R6 Δ, lacking the main enzyme involved in oxygen peroxide production, than in R6. Although no change in the recovery of chromosome fragmentation was observed between R6 and R6 Δ, 3.5 × 10-fold lower reactive oxygen species production was observed in R6 Δ, without changes after drug removal. These results show that reactive oxygen species are the main factors directing the postantibiotic effect of levofloxacin and moxifloxacin in .
我们研究了左氧氟沙星和莫西沙星在野生型菌株 R6 中的抗生素后效应的分子机制。左氧氟沙星在 2.5×和 10×MIC 时的抗生素后效应分别为 2.05±0.10 h（平均值±标准偏差[SD]）和 3.23±0.45 h。莫西沙星的效应较低，分别为 2.5×和 10×MIC 时的 0.87±0.1 和 2.41±0.29 h。在左氧氟沙星（2.5×MIC）和莫西沙星（10×MIC）的等效抗生素后效应下，测量了氟喹诺酮诱导的染色体碎片化。在药物去除 2 小时后，左氧氟沙星的减少约为 7 倍，莫西沙星的减少约为 3 倍，随后的时间没有进一步减少。在药物撤出 4 至 6 小时后检测到活性氧物质的产生变化，左氧氟沙星的减少≥400 倍，莫西沙星的减少≥800 倍，在 6 小时时。相应地，在药物撤出 4 至 6 小时后，左氧氟沙星诱导的 操纵子上调，将铁引入细菌，减少了 2 至 3 倍，莫西沙星诱导的与丙酮酸生产有关的几个基因的上调减少了 3 至 7 倍。相应地，在缺乏主要参与过氧化物产生的酶的 R6Δ菌株中观察到的抗生素后效应（最长 1 h）低于 R6。虽然在 R6 和 R6Δ之间没有观察到染色体碎片化恢复的变化，但在 R6Δ中观察到活性氧物质的产生降低了 3.5×10 倍，药物去除后没有变化。这些结果表明，活性氧物质是左氧氟沙星和莫西沙星在 中的抗生素后效应的主要因素。
