Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases.
Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases.
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DOI：
10.1038/srep11827
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发表时间：
2015-07-14
影响因子：
4.6
通讯作者：
Newman JV
中科院分区：
文献类型：
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作者：
Basarab GS;Kern GH;McNulty J;Mueller JP;Lawrence K;Vishwanathan K;Alm RA;Barvian K;Doig P;Galullo V;Gardner H;Gowravaram M;Huband M;Kimzey A;Morningstar M;Kutschke A;Lahiri SD;Perros M;Singh R;Schuck VJ;Tommasi R;Walkup G;Newman JV
随着当前抗菌疗法的有效性不断降低，发现一种通过规避现有耐药性的机制运作的药物是至关重要的。ETX0914是一种针对淋病治疗的新型抗菌剂中的第一种，它通过一种新的抑制模式对细菌II型拓扑异构酶起作用。在支架上加入恶唑烷酮减轻了拓扑异构酶抑制剂常出现的毒理学问题。对其他拓扑异构酶抑制剂耐药的生物体与ETX0914没有交叉耐药，ETX0914的自发耐药突变体与其他拓扑异构酶抑制剂（包括广泛使用的氟喹诺酮类）也没有交叉耐药。ETX0914的药代动力学和药效学临床前评估显示其在小鼠金黄色葡萄球菌感染模型中的分布和疗效，该模型可作为预测淋病奈瑟菌感染治疗有效暴露的替代方法。毒理学评估中有效暴露的广泛安全边际支持进展到1期。在人类志愿者中使用ETX0914显示出足够的暴露量和最小的不良反应，期望一种高效的抗淋病治疗。
With the diminishing effectiveness of current antibacterial therapies, it is critically important to discover agents that operate by a mechanism that circumvents existing resistance. ETX0914, the first of a new class of antibacterial agent targeted for the treatment of gonorrhea, operates by a novel mode-of-inhibition against bacterial type II topoisomerases. Incorporating an oxazolidinone on the scaffold mitigated toxicological issues often seen with topoisomerase inhibitors. Organisms resistant to other topoisomerase inhibitors were not cross-resistant with ETX0914 nor were spontaneous resistant mutants to ETX0914 cross-resistant with other topoisomerase inhibitor classes, including the widely used fluoroquinolone class. Preclinical evaluation of ETX0914 pharmacokinetics and pharmacodynamics showed distribution into vascular tissues and efficacy in a murine Staphylococcus aureus infection model that served as a surrogate for predicting efficacious exposures for the treatment of Neisseria gonorrhoeae infections. A wide safety margin to the efficacious exposure in toxicological evaluations supported progression to Phase 1. Dosing ETX0914 in human volunteers showed sufficient exposure and minimal adverse effects to expect a highly efficacious anti-gonorrhea therapy.