Developing Cyclic Peptomers as Broad-Spectrum Type III Secretion System Inhibitors in Gram-Negative Bacteria.
Developing Cyclic Peptomers as Broad-Spectrum Type III Secretion System Inhibitors in Gram-Negative Bacteria.
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DOI：
10.1128/aac.01690-20
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发表时间：
2021-06-17
影响因子：
4.9
通讯作者：
Auerbuch V
中科院分区：
文献类型：
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作者：
Lam HN;Lau T;Lentz A;Sherry J;Cabrera-Cortez A;Hug K;Lalljie A;Engel J;Lokey RS;Auerbuch V
抗生素耐药性细菌是一种新兴的全球健康威胁。迫切需要新的抗菌剂。注射体III型分泌系统（T3 SS）是一种有吸引力的抗菌靶标，其为数十种革兰氏阴性细菌的毒力所需，但在非致病性细菌中基本上不存在。我们先前鉴定了受天然产物去甲氨肽酶D启发的合成环状肽异构体，其抑制通过耶尔森氏菌Ysc和铜绿假单胞菌Psc T3 SS的蛋白质分泌，但不抑制细菌生长。在这里，我们描述了一种异构体4 EpDN的鉴定，其效力是其母体化合物的2倍（50%抑制浓度[IC 50]为4 μM）。此外，4 EpDN抑制耶尔森氏菌Ysa和沙门氏菌SPI-1 T3 SS，表明这种环状肽异构体对进化上遥远的注射体T3 SS具有广泛的功效。事实上，4 EpDN强烈抑制了HeLa细胞中沙眼衣原体的细胞内生长，这需要T3 SS。4 EpDN不抑制非亲缘双生子精氨酸易位（达特）系统，也不影响T3 SS基因的转录。此外，尽管注射体和鞭毛T3 SS在进化上和结构上相关，但4 EpDN环状肽异构体并不抑制底物通过沙门氏菌鞭毛T3 SS的分泌，表明环状肽异构体广泛但特异性地靶向注射体T3 SS。4 EpDN可减少假结核耶尔森氏菌表面T3 SS针的数量。总的来说，这些数据表明，环状肽异构体特异性地抑制来自各种革兰氏阴性细菌的注射体T3 SS，可能是通过阻止完全的T3 SS组装。
Antibiotic-resistant bacteria are an emerging global health threat. New antimicrobials are urgently needed. The injectisome type III secretion system (T3SS), required by dozens of Gram-negative bacteria for virulence but largely absent from nonpathogenic bacteria, is an attractive antimicrobial target. We previously identified synthetic cyclic peptomers, inspired by the natural product phepropeptin D, that inhibit protein secretion through the Yersinia Ysc and Pseudomonas aeruginosa Psc T3SSs but do not inhibit bacterial growth. Here, we describe the identification of an isomer, 4EpDN, that is 2-fold more potent (50% inhibitory concentration [IC50] of 4 μM) than its parental compound. Furthermore, 4EpDN inhibited the Yersinia Ysa and the Salmonella SPI-1 T3SSs, suggesting that this cyclic peptomer has broad efficacy against evolutionarily distant injectisome T3SSs. Indeed, 4EpDN strongly inhibited intracellular growth of Chlamydia trachomatis in HeLa cells, which requires the T3SS. 4EpDN did not inhibit the unrelated twin arginine translocation (Tat) system, nor did it impact T3SS gene transcription. Moreover, although the injectisome and flagellar T3SSs are evolutionarily and structurally related, the 4EpDN cyclic peptomer did not inhibit secretion of substrates through the Salmonella flagellar T3SS, indicating that cyclic peptomers broadly but specifically target the injectisome T3SS. 4EpDN reduced the number of T3SS needles detected on the surface of Yersinia pseudotuberculosis as detected by microscopy. Collectively, these data suggest that cyclic peptomers specifically inhibit the injectisome T3SS from a variety of Gram-negative bacteria, possibly by preventing complete T3SS assembly.