One cannot rule them all: Are bacterial toxins-antitoxins druggable?
One cannot rule them all: Are bacterial toxins-antitoxins druggable?
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DOI：
10.1093/femsre/fuv002
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发表时间：
2015-07
影响因子：
11.3
通讯作者：
Espinosa M
中科院分区：
文献类型：
--
作者：
Chan WT;Balsa D;Espinosa M
第二类(蛋白)毒素-抗毒素(TA)操纵子广泛存在于细菌和古生菌中。它们被组织成操纵子，通常，在操纵子中，抗毒素基因先于同源毒素基因。抗毒素通常作为转录自抑制因子发挥作用，而毒素则作为共抑制因子发挥作用，这两种蛋白质都构成无害的复合体。当细菌遇到有压力的环境时，TA就会被触发。抗毒素蛋白是不稳定的，会被宿主酶降解，释放出游离毒素来停止必要的过程。结果是细胞停止生长，甚至死亡。由于其无处不在和靶向的基本过程，TA已被认为是开发新型抗菌剂的良好候选者。我们在这里讨论了TA作为抗病毒药物和抗菌药物的可能的药效性，重点讨论了它们在现实世界中使用的潜力和挑战。鉴于新的技术，例如使用非常小的分子(片段)作为蛋白质-蛋白质相互作用的抑制剂，我们提出了开发TA作为抗菌药物的策略。适当的片段可能会破坏T：A接口，导致靶TA对的释放。本文还讨论了TAS的可能给药途径和剂型。我们认为开发II型家族毒素的各种方法可能是药物发现的候选；毒素的可药性--抗毒素可能作为抗病毒药物。作为抗菌药，它们可能被认为是可用药，但到目前为止，给药和配方可能并不简单。我们认为开发II型家族毒素的各种方法可能是药物发现的候选；毒素的可药性--抗毒素可能作为抗病毒药物。作为抗菌药，它们可能被认为是可用药，但到目前为止，给药和配方可能并不简单。
Type II (proteic) toxin–antitoxin (TA) operons are widely spread in bacteria and archaea. They are organized as operons in which, usually, the antitoxin gene precedes the cognate toxin gene. The antitoxin generally acts as a transcriptional self-repressor, whereas the toxin acts as a co-repressor, both proteins constituting a harmless complex. When bacteria encounter a stressful environment, TAs are triggered. The antitoxin protein is unstable and will be degraded by host proteases, releasing the free toxin to halt essential processes. The result is a cessation of cell growth or even death. Because of their ubiquity and the essential processes targeted, TAs have been proposed as good candidates for development of novel antimicrobials. We discuss here the possible druggability of TAs as antivirals and antibacterials, with focus on the potentials and the challenges that their use may find in the ‘real’ world. We present strategies to develop TAs as antibacterials in view of novel technologies, such as the use of very small molecules (fragments) as inhibitors of protein–protein interactions. Appropriate fragments could disrupt the T:A interfaces leading to the release of the targeted TA pair. Possible ways of delivery and formulation of Tas are also discussed. We consider various approaches to develop the toxins of the type II family as possible candidates to drug discovery; druggability of toxins-antitoxins could be possible as antivirals. As antibacterials, they might be considered as druggable but delivery and formulation may not be simple so far. We consider various approaches to develop the toxins of the type II family as possible candidates to drug discovery; druggability of toxins-antitoxins could be possible as antivirals. As antibacterials, they might be considered as druggable but delivery and formulation may not be simple so far.
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影响因子：
4.2
作者：
Chono, Hideto;Matsumoto, Kazuya;Kato, Ikunoshin
通讯作者：
Kato, Ikunoshin
影响因子：
4.8
作者：
Brown, Breann L.;Lord, Dana M.;Page, Rebecca
通讯作者：
Page, Rebecca
DOI：
10.1016/j.str.2012.08.017
发表时间：
2012-10-10
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Bøggild A;Sofos N;Andersen KR;Feddersen A;Easter AD;Passmore LA;Brodersen DE
通讯作者：
Brodersen DE
DOI：
10.1016/j.str.2010.04.018
发表时间：
2010-08-11
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Arbing MA;Handelman SK;Kuzin AP;Verdon G;Wang C;Su M;Rothenbacher FP;Abashidze M;Liu M;Hurley JM;Xiao R;Acton T;Inouye M;Montelione GT;Woychik NA;Hunt JF
通讯作者：
Hunt JF
DOI：
10.1073/pnas.251327898
发表时间：
2001-12-04
影响因子：
11.1
作者：
Christensen, SK;Mikkelsen, M;Gerdes, K
通讯作者：
Gerdes, K