Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS One. 2010 Dec 8;5(12):e15179. doi: 10.1371/journal.pone.0015179.
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.
抗生素通过为耐药菌株提供竞争优势，从而增加了耐药菌的频率。在这里，我们开发了一种通用的竞争性抑制微生物菌株的化学抑制分析方法，并利用该方法来鉴定优先抑制四环素耐药菌而不是敏感菌的化合物，从而“反转”耐药性选择。我们的分析方法区分了直接针对特定耐药机制的化合物和那些基于与四环素的生理相互作用而选择耐药性的化合物，并且在耐药机制方面更加通用。一个初步筛选表明，这两种类型的反转选择化合物都是由土壤微生物分泌的，这表明自然界已经进化出了一系列可以对抗抗生素耐药性的化学物质。最后，我们表明，我们的分析方法可以更一般地允许根据不同菌株或靶标对药物的差异活性进行简单、直接的筛选。
