Facilitating Compound Entry as a Means to Discover Antibiotics for Gram-Negative Bacteria.
Facilitating Compound Entry as a Means to Discover Antibiotics for Gram-Negative Bacteria.
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DOI：
10.1021/acs.accounts.0c00895
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发表时间：
2021-03-16
影响因子：
18.3
通讯作者：
Hergenrother PJ
中科院分区：
文献类型：
--
作者：
Muñoz KA;Hergenrother PJ
自美国食品和药物管理局(FDA)批准对最有问题的革兰氏阴性菌起作用的最后一类抗生素以来，已经有半个多世纪了。开发抗生素治疗这些感染的主要挑战不是药物靶标的结合，而是大多数小分子无法穿过革兰氏阴性膜，被保留并在细胞内积累。尽管有丰富的先导化合物，但对革兰氏阴性菌积累(或避免外排)化合物所需的物理化学性质的有限了解，阻碍了开发革兰氏阴性抗生素的普遍方法。事实上，在许多情况下，尽管进行了多年密集的衍生化努力，并合成了数百种旨在增强革兰氏阴性活性的化合物，但在扩大许多革兰氏阳性抗生素的活性范围方面几乎或没有取得任何进展。在本文中，我们描述了一种有前景的策略的发现和成功应用，该策略用于增强仅对革兰氏阳性的抗生素的积累，作为一种注入具有广谱活性的化合物的手段。利用一种前瞻性的方法研究了180多种不同化合物在大肠杆菌中的积累，我们发现，当小分子含有可电离的氮、低三维和刚性时，它们在大肠杆菌中积累的可能性增加。执行这些被称为“进入规则”的指南，并在网络应用程序www.Entry-way.org的帮助下，我们促进了化合物的进入，并系统地将革兰氏阴性活性建立在仅限革兰氏阳性的抗生素中。虽然每种抗生素都有具体情况的考虑，但我们描述了一组重要的标准，当通过参赛规则选择仅革兰氏阳性的候选抗生素转换为革兰氏阴性活性版本时要考虑的一组重要标准。如本文详细介绍的那样，使用这一蓝图，扩大了三种抗生素类别的活性谱，这三类抗生素涉及三种不同的生物靶点：DNA旋转酶抑制剂6DNM、Fabi抑制剂DeBIO-1452和FMN核糖开关抑制剂RiboseyC。在每种情况下，条目规则指导容易在革兰氏阴性细菌中积累的关键类似物的合成，从而产生对大肠杆菌和其他革兰氏阴性ESKAPE病原体显示抗生素活性(最低抑制浓度≤8μg mLESKAPE 1)的化合物。虽然随着收集更多的累积数据，条目规则将继续改进和增强，但根据这些集体结果和本文未涵盖的其他例子，显然条目规则对于从仅有革兰氏阳性化合物开发新型广谱抗生素是可行的。通过能够预测化合物的积累，条目规则应该有助于发现和开发有效对抗革兰氏阴性细菌的新抗生素的过程。
It has been over half a century since the last class of antibiotics active against the most problematic Gram-negative bacteria was approved by the Food and Drug Administration (FDA). The major challenge with developing antibiotics to treat these infections is not drug—target engagement, but rather the inability of most small molecules to traverse the Gram-negative membranes, be retained, and accumulate within the cell. Despite an abundance of lead compounds, limited understanding of the physicochemical properties needed for compound accumulation (or avoidance of efflux) in Gram-negative bacteria has precluded a generalizable approach for developing Gram-negative antibiotics. Indeed, in many instances, despite years of intensive derivatization efforts and the synthesis of hundreds of compounds aimed at building-in Gram-negative activity, little or no progress has been made in expanding the spectrum of activity for many Gram-positive-only antibiotics. In this Account, we describe the discovery and successful applications of a promising strategy for enhancing accumulation of Gram-positive-only antibiotics as a means of imbuing compounds with broad-spectrum activity. Utilizing a prospective approach examining accumulation in Escherichia coli for over 180 diverse compounds, we found that small molecules have an increased likelihood to accumulate in E. coli when they contain an ionizable Nitrogen, have low Three-dimensionality, and are Rigid. Implementing these guidelines, codified as the “eNTRy rules” and assisted by the web application www.entry-way.org, we have facilitated compound entry and systematically built Gram-negative activity into Gram-positive-only antibiotics. Though each antibiotic will have case-specific considerations, we describe a set of important criteria to consider when selecting candidate Gram-positive-only antibiotics for conversion to Gram-negative active versions via the eNTRy rules. As detailed herein, using this blueprint the spectrum of activity was expanded for three antibiotic classes that engage three different biological targets: DNA gyrase inhibitor 6DNM, FabI inhibitor Debio-1452, and FMN riboswitch inhibitor Ribocil C. In each scenario, the eNTRy rules guided the synthesis of key analogues predisposed to accumulate in Gram-negative bacteria leading to compounds that display antibiotic activity (minimum inhibitory concentrations ≤ 8 μg mL−1) against E. coli and other Gram-negative ESKAPE pathogens. While the eNTRy rules will continue to be refined and enhanced as more accumulation data is gathered, based on these collective results and on other examples not covered herein, it is clear that the eNTRy rules are actionable for the development of novel broad-spectrum antibiotics from Gram-positive-only compounds. By enabling prediction of compound accumulation, the eNTRy rules should facilitate the process of discovering and developing novel antibiotics active against Gram-negative bacteria.
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影响因子：
4
作者：
Davis, Tony D.;Gerry, Christopher J.;Tan, Derek S.
通讯作者：
Tan, Derek S.
DOI：
10.1111/j.1476-5381.1962.tb01416.x
发表时间：
1962-01-01
期刊：
BRITISH JOURNAL OF PHARMACOLOGY AND CHEMOTHERAPY
影响因子：
--
作者：
ACRED, P;TURNER, DH;BROWN, DM
通讯作者：
BROWN, DM
影响因子：
6.4
作者：
Brooks LE;Ul-Hasan S;Chan BK;Sistrom MJ
通讯作者：
Sistrom MJ
影响因子：
4.8
作者：
Hoffman, Paul S.
通讯作者：
Hoffman, Paul S.
影响因子：
7.3
作者：
Andrews, Logan D.;Kane, Timothy R.;Cohen, Frederick
通讯作者：
Cohen, Frederick