Discovery and Mechanistic Analysis of Structurally Diverse Inhibitors of Acetyltransferase Eis among FDA-Approved Drugs.
Discovery and Mechanistic Analysis of Structurally Diverse Inhibitors of Acetyltransferase Eis among FDA-Approved Drugs.
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DOI：
10.1021/acs.biochem.2c00658
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发表时间：
2023-01
期刊：
影响因子：
2.9
通讯作者：
A. Pang;Keith D. Green;A. Punetha;Nishad Thamban Chandrika;Kaitlind C Howard;S. Garneau‐Tsodikova;O. Tsodikov
中科院分区：
文献类型：
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作者：
A. Pang;Keith D. Green;A. Punetha;Nishad Thamban Chandrika;Kaitlind C Howard;S. Garneau‐Tsodikova;O. Tsodikov
每年有150多万人死于结核病。耐多药结核病感染尤其危险，需要新的药物来对抗它们。药物开发的高成本和复杂性使得已经在临床上用于其他适应症的药物的重新定位成为一种潜在的节省时间和金钱的途径。在这项研究中，我们确定了现有的药物中的五种化合物：氮卓斯汀，文拉法辛，氯喹，甲氟喹，和氯胍作为乙酰转移酶Eis的抑制剂从结核分枝杆菌，结核病的病原体。Eis上调是TB对卡那霉素的临床相关耐药性的原因，卡那霉素通过Eis催化的乙酰化而失活。这些药物以及与Eis复合的氯己定的晶体结构表明，这些抑制剂结合在氨基糖苷类结合腔中，与其相对于卡那霉素的既定抑制模式一致。在另外合成的三种化合物中，根据氯胍-氯胍复合物的晶体结构设计的氯胍类似物比氯胍有效3倍。这些化合物与Eis复合物的晶体结构解释了它们的抑制效力。这些在合理药物重新定位方面的初步努力可以作为进一步开发Eis抑制剂的起点。
Over one and a half million people die of tuberculosis (TB) each year. Multidrug-resistant TB infections are especially dangerous, and new drugs are needed to combat them. The high cost and complexity of drug development make repositioning of drugs that are already in clinical use for other indications a potentially time- and money-saving avenue. In this study, we identified among existing drugs five compounds: azelastine, venlafaxine, chloroquine, mefloquine, and proguanil as inhibitors of acetyltransferase Eis from Mycobacterium tuberculosis, a causative agent of TB. Eis upregulation is a cause of clinically relevant resistance of TB to kanamycin, which is inactivated by Eis-catalyzed acetylation. Crystal structures of these drugs as well as chlorhexidine in complexes with Eis showed that these inhibitors were bound in the aminoglycoside binding cavity, consistent with their established modes of inhibition with respect to kanamycin. Among three additionally synthesized compounds, a proguanil analogue, designed based on the crystal structure of the Eis-proguanil complex, was 3-fold more potent than proguanil. The crystal structures of these compounds in complexes with Eis explained their inhibitory potencies. These initial efforts in rational drug repositioning can serve as a starting point in further development of Eis inhibitors.