The RecX protein, a very active natural RecA protein inhibitor, can completely disassemble RecA filaments at nanomolar concentrations that are two to three orders of magnitude lower than that of RecA protein. Based on the structure of RecX protein complex with the presynaptic RecA filament, we designed a short first in class α-helical peptide that both inhibits RecA protein activities in vitro and blocks the bacterial SOS-response in vivo. The peptide was designed using SEQOPT, a novel method for global sequence optimization of protein α-helices. SEQOPT produces artificial peptide sequences containing only 20 natural amino acids with the maximum possible conformational stability at a given pH, ionic strength, temperature, peptide solubility. It also accounts for restrictions due to known amino acid residues involved in stabilization of protein complexes under consideration. The results indicate that a few key intermolecular interactions inside the RecA protein presynaptic complex are enough to reproduce the main features of the RecX protein mechanism of action. Since the SOS-response provides a major mechanism of bacterial adaptation to antibiotics, these results open new ways for the development of antibiotic co-therapy that would not cause bacterial resistance.

中文翻译：

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用短α螺旋肽阻断细菌的RecA活性和SOS反应

RecX蛋白是一种非常活跃的天然RecA蛋白抑制剂，可以在纳摩尔浓度（比RecA蛋白低2-3个数量级）的情况下完全分解RecA细丝。基于RecX蛋白复合物与突触前的RecA长丝的结构，我们设计了一个短的第一类α螺旋肽，这两个抑制RecA的蛋白质活性的体外和块中的细菌SOS响应体内。使用SEQOPT设计肽段，SEQOPT是一种用于蛋白质α螺旋全局序列优化的新方法。SEQOPT产生的人工肽序列仅包含20个天然氨基酸，在给定的pH，离子强度，温度，肽溶解度下具有最大可能的构象稳定性。它还考虑到由于已知氨基酸残基参与所考虑的蛋白质复合物的稳定化而造成的限制。结果表明，RecA蛋白突触前复合体内的一些关键的分子间相互作用足以重现RecX蛋白作用机理的主要特征。由于SOS反应提供了细菌对抗生素的适应的主要机制，因此这些结果为开发不会引起细菌抗药性的抗生素联合疗法开辟了新途径。