A differential drug screen for compounds that select against antibiotic resistance.
A differential drug screen for compounds that select against antibiotic resistance.
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DOI：
10.1371/journal.pone.0015179
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发表时间：
2010-12-08
期刊：
影响因子：
3.7
通讯作者：
Kishony R
中科院分区：
文献类型：
--
作者：
Chait R;Shrestha S;Shah AK;Michel JB;Kishony R
抗生素为耐药细菌提供了相对于敏感菌株的竞争优势，从而增加了耐药细菌的出现频率。在这里，我们开发了一种通用的竞争微生物菌株的差异化学抑制试验，并用它来鉴定相对于敏感细菌优先抑制四环素耐药性的化合物，从而“逆转”耐药性选择。我们的方法区分了直接针对特定抗性机制进行选择的化合物和基于其与四环素的生理相互作用而进行抗药性选择的化合物，在抗性机制方面更具一般性。中试筛选表明，这两种类型的选择逆转化合物都是由土壤微生物分泌的，这表明大自然已经进化出了一系列能够抵消抗生素耐药性的化学物质。最后，我们表明，我们的检测方法可以更普遍地根据药物对不同菌株或靶标的不同活性进行简单、直接的筛选。
Antibiotics increase the frequency of resistant bacteria by providing them a competitive advantage over sensitive strains. Here, we develop a versatile assay for differential chemical inhibition of competing microbial strains, and use it to identify compounds that preferentially inhibit tetracycline-resistant relative to sensitive bacteria, thus “inverting” selection for resistance. Our assay distinguishes compounds selecting directly against specific resistance mechanisms and compounds whose selection against resistance is based on their physiological interaction with tetracycline and is more general with respect to resistance mechanism. A pilot screen indicates that both types of selection-inverting compounds are secreted by soil microbes, suggesting that nature has evolved a repertoire of chemicals that counteracts antibiotic resistance. Finally, we show that our assay can more generally permit simple, direct screening for drugs based on their differential activity against different strains or targets.
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