Mannitol enhances antibiotic sensitivity of persister bacteria in Pseudomonas aeruginosa biofilms.
Mannitol enhances antibiotic sensitivity of persister bacteria in Pseudomonas aeruginosa biofilms.
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DOI：
10.1371/journal.pone.0084220
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Rice SA
中科院分区：
文献类型：
--
作者：
Barraud N;Buson A;Jarolimek W;Rice SA
抗生素治疗未能清除铜绿假单胞菌肺部感染（囊性纤维化（CF）患者的关键死亡因素），部分原因是铜绿假单胞菌生物膜的高耐受性。先前已发现甘露醇通过产生质子动力（PMF）恢复大肠杆菌中氨基糖苷类药物的敏感性，这表明了改善CF抗生素治疗和减少疾病进展的潜在新策略。在这里，我们使用常用的氨基糖苷类妥布霉素来选择生物膜生长期间的铜绿假单胞菌持久细胞。用甘露醇（10-40 mM）孵育使耐药细胞的妥布霉素敏感性增加高达1，000倍。向预生长的生物膜中添加甘露醇能够逆转持续表型并提高妥布霉素的功效。这种作用通过添加PMF抑制剂或在不能代谢甘露醇的铜绿假单胞菌突变株中被阻断。在高渗透压下加入葡萄糖和NaCl也可改善妥布霉素的疗效，尽管与甘露醇相比程度较低。因此，甘露醇在恢复生物膜相关持留细胞中的主要作用似乎是一种主动的生理反应，与渗透压的微小贡献相关。甘露醇对临床相关菌株进行了测试，表明含有持留细胞亚群的生物膜在甘露醇存在下被更好地杀死，但对妥布霉素具有高抗性的临床菌株不受甘露醇的影响。总体而言，这些结果表明，除了通过促进CF中的粘液清除来改善肺功能外，甘露醇还影响生物膜中的抗生素敏感性，并通过主动生理反应来实现。
The failure of antibiotic therapies to clear Pseudomonas aeruginosa lung infection, the key mortality factor for cystic fibrosis (CF) patients, is partly attributed to the high tolerance of P. aeruginosa biofilms. Mannitol has previously been found to restore aminoglycoside sensitivity in Escherichia coli by generating a proton-motive force (PMF), suggesting a potential new strategy to improve antibiotic therapy and reduce disease progression in CF. Here, we used the commonly prescribed aminoglycoside tobramycin to select for P. aeruginosa persister cells during biofilm growth. Incubation with mannitol (10–40 mM) increased tobramycin sensitivity of persister cells up to 1,000-fold. Addition of mannitol to pre-grown biofilms was able to revert the persister phenotype and improve the efficacy of tobramycin. This effect was blocked by the addition of a PMF inhibitor or in a P. aeruginosa mutant strain unable to metabolise mannitol. Addition of glucose and NaCl at high osmolarity also improved the efficacy of tobramycin although to a lesser extent compared to mannitol. Therefore, the primary effect of mannitol in reverting biofilm associated persister cells appears to be an active, physiological response, associated with a minor contribution of osmotic stress. Mannitol was tested against clinically relevant strains, showing that biofilms containing a subpopulation of persister cells are better killed in the presence of mannitol, but a clinical strain with a high resistance to tobramycin was not affected by mannitol. Overall, these results suggest that in addition to improvements in lung function by facilitating mucus clearance in CF, mannitol also affects antibiotic sensitivity in biofilms and does so through an active, physiological response.
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影响因子：
5.7
作者：
Barraud N;Storey MV;Moore ZP;Webb JS;Rice SA;Kjelleberg S
通讯作者：
Kjelleberg S
DOI：
10.1056/nejmra0910061
发表时间：
2010-12-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Fahy JV;Dickey BF
通讯作者：
Dickey BF
影响因子：
6.7
作者：
Dawson CC;Intapa C;Jabra-Rizk MA
通讯作者：
Jabra-Rizk MA
影响因子：
4.5
作者：
Bernier SP;Lebeaux D;DeFrancesco AS;Valomon A;Soubigou G;Coppée JY;Ghigo JM;Beloin C
通讯作者：
Beloin C
影响因子：
6.7
作者：
Hoffman LR;Richardson AR;Houston LS;Kulasekara HD;Martens-Habbena W;Klausen M;Burns JL;Stahl DA;Hassett DJ;Fang FC;Miller SI
通讯作者：
Miller SI