Clinically Relevant Growth Conditions Alter Acinetobacter baumannii Antibiotic Susceptibility and Promote Identification of Novel Antibacterial Agents.
Clinically Relevant Growth Conditions Alter Acinetobacter baumannii Antibiotic Susceptibility and Promote Identification of Novel Antibacterial Agents.
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DOI：
10.1371/journal.pone.0143033
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Dunman PM
中科院分区：
文献类型：
--
作者：
Colquhoun JM;Wozniak RA;Dunman PM
在宿主环境中控制细菌增殖和生存的生物过程可能与在营养丰富的实验室培养基中生存所需的生物过程有很大不同(S)。因此，在模拟细菌疾病状态方面的条件下进行的基于生长的抗菌素筛选有可能识别出常规实验室介质中进行的筛选所遗漏的新类别的抗菌剂。因此，我们对853种FDA批准的药物的Selleck文库进行了筛选，以寻找在人血清、肺表面活性物质和/或生物被膜状态下的生物体中对革兰氏阴性细菌病原体鲍曼不动杆菌表现出抗菌活性的药物，并将这些结果与传统实验室培养基相比较。结果显示，在至少一种筛选条件下，总共有代表73种抗生素的90种化合物和为替代治疗适应症开发的17种药物对测试菌株显示出抗菌特性。在有效的抗生素库中，只有4种抗生素，利福平、利福昔明、环丙沙星和四环素在所有筛选条件下对微生物显示出抗菌活性，而其余的在≥1条件下不起作用；56种抗生素在血清生长过程中不起作用，25种和38种抗生素分别对肺表面活性物质生长和生物膜相关细胞不起作用，这表明在不同的感染环境下，抗生素亚类可能表现出更好的抗菌活性。此外，9种主要用于治疗革兰氏阳性菌的抗生素和10种非抗生素对在常规培养条件下生长的鲍曼不动杆菌没有检测到的抗菌活性，但在≥1替代生长条件下具有活性(S)。这些药物可能代表着很有前途的抗不动杆菌药物，而在传统的实验室筛选介质中进行的抗微生物全细胞筛选试验很可能会忽视这些药物。
Biological processes that govern bacterial proliferation and survival in the host-environment(s) are likely to be vastly different from those that are required for viability in nutrient-rich laboratory media. Consequently, growth-based antimicrobial screens performed in conditions modeling aspects of bacterial disease states have the potential to identify new classes of antimicrobials that would be missed by screens performed in conventional laboratory media. Accordingly, we performed screens of the Selleck library of 853 FDA approved drugs for agents that exhibit antimicrobial activity toward the Gram-negative bacterial pathogen Acinetobacter baumannii during growth in human serum, lung surfactant, and/or the organism in the biofilm state and compared those results to that of conventional laboratory medium. Results revealed that a total of 90 compounds representing 73 antibiotics and 17 agents that were developed for alternative therapeutic indications displayed antimicrobial properties toward the test strain in at least one screening condition. Of the active library antibiotics only four agents, rifampin, rifaximin, ciprofloxacin and tetracycline, exhibited antimicrobial activity toward the organism during all screening conditions, whereas the remainder were inactive in ≥ 1 condition; 56 antibiotics were inactive during serum growth, 25 and 38 were inactive toward lung surfactant grown and biofilm-associated cells, respectively, suggesting that subsets of antibiotics may outperform others in differing infection settings. Moreover, 9 antibiotics that are predominantly used for the treatment Gram-positive pathogens and 10 non-antibiotics lacked detectable antimicrobial activity toward A. baumannii grown in conventional medium but were active during ≥ 1 alternative growth condition(s). Such agents may represent promising anti-Acinetobacter agents that would have likely been overlooked by antimicrobial whole cell screening assays performed in traditional laboratory screening media.