Harnessing Rare Actinomycete Interactions and Intrinsic Antimicrobial Resistance Enables Discovery of an Unusual Metabolic Inhibitor.
Harnessing Rare Actinomycete Interactions and Intrinsic Antimicrobial Resistance Enables Discovery of an Unusual Metabolic Inhibitor.
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作者：
细菌天然产物在历史上一直是新药的深层来源，但近几十年来，它们的缓慢发现使开发提高捕获新化合物的可能性的策略变得更加重要。在这里，我们使用了一种直接的方法，利用了“稀有”放线菌的相互作用生态学。具体来说，我们筛选了引发抗菌剂产生的相互作用，这些抗菌剂抑制了具有异常多样的天然抗菌剂耐药性的细菌菌株的生长。这一策略导致了一个家族的抗菌剂的发现，我们称之为dynaplanins。异源表达使得能够鉴定dynaplanin生物合成基因簇，其被用于天然产物基因簇检测的典型算法错过。部分耐药突变体的基因组测序揭示了2-含氧酸脱氢酶E2亚基作为动力素的可能分子靶点，这一发现得到了该酶活性位点内动力素支架的计算建模的支持。因此，这种利用微生物相互作用和天然抗生素抗性的简单策略可以发现具有独特抗菌活性的分子。此外，这些结果表明，初级代谢可能是通过化学干扰竞争性微生物相互作用抑制的直接目标。
Bacterial natural products have historically been a deep source of new medicines, but their slowed discovery in recent decades has put a premium on developing strategies that enhance the likelihood of capturing novel compounds. Here, we used a straightforward approach that capitalizes on the interactive ecology of “rare” actinomycetes. Specifically, we screened for interactions that triggered the production of antimicrobials that inhibited the growth of a bacterial strain with exceptionally diverse natural antimicrobial resistance. This strategy led to the discovery of a family of antimicrobials we term the dynaplanins. Heterologous expression enabled identification of the dynaplanin biosynthetic gene cluster, which was missed by typical algorithms for natural product gene cluster detection. Genome sequencing of partially resistant mutants revealed a 2-oxo acid dehydrogenase E2 subunit as the likely molecular target of the dynaplanins, and this finding was supported by computational modeling of the dynaplanin scaffold within the active site of this enzyme. Thus, this simple strategy, which leverages microbial interactions and natural antibiotic resistance, can enable discovery of molecules with unique antimicrobial activity. In addition, these results indicate that primary metabolism may be a direct target for inhibition via chemical interference in competitive microbial interactions.
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影响因子：
5.2
作者：
de la Cruz M;González I;Parish CA;Onishi R;Tormo JR;Martín J;Peláez F;Zink D;El Aouad N;Reyes F;Genilloud O;Vicente F
通讯作者：
Vicente F
影响因子：
48
作者：
Gibson, Daniel G.;Young, Lei;Smith, Hamilton O.
通讯作者：
Smith, Hamilton O.
DOI：
10.1023/a:1026579426265
发表时间：
2000-08-01
影响因子：
2.6
作者：
Hayakawa, M;Otoguro, M;Iimura, Y
通讯作者：
Iimura, Y
DOI：
10.1073/pnas.1934677100
发表时间：
2003-11-25
影响因子：
11.1
作者：
Challis, GL;Hopwood, DA
通讯作者：
Hopwood, DA
影响因子：
4.9
作者：
Guitor, Allison K.;Raphenya, Amogelang R.;Wright, Gerard D.
通讯作者：
Wright, Gerard D.