美国Entasis Therapeutics的Ruben A. Tommasi研究组进行了感染耐药新型抗生素的合理设计。这一研究成果于2021年9月15日发表在国际顶尖学术期刊《自然》上。

他描述了一种革兰氏阴性菌青霉素结合蛋白的二氮杂双环辛烷抑制剂的合理设计方案，以克服多种耐药机制，包括β-内酰胺酶、严格反应和外膜渗透。二氮杂双环辛烷抑制剂在β-内酰胺酶存在时仍保持活性，β-内酰胺酶是革兰氏阴性菌β-内酰胺治疗相关的主要耐药机制。尽管成功地重新设计了初始铅靶标光谱以获得体内功效，但其渗透细菌外膜的能力不足以进行进一步的开发。

值得注意的是，增强靶标效力的特征阻止了化合物的吸收。改进的优化策略在先导优化阶段利用了孔蛋白渗透特性以及生化效力。因此产生了 ETX0462，它对铜绿假单胞菌和所有其他革兰氏阴性 ESKAPE 病原体、嗜麦芽窄食单胞菌和生物威胁病原体具有有效的体外和体内活性。这些特性以及良好的临床前安全性，为 25 年来首个治疗危及生命的抗生素耐药性感染的新型革兰氏阴性化学型的成功临床开发提供了希望。

据了解，随着抗生素耐药性在全球范围内不断增加，亟待开发新的抗生素来治疗由耐药革兰氏阴性病原体引起的感染。

附：英文原文

Title: Rational design of a new antibiotic class for drug-resistant infections

Author: Durand-Reville, Thomas F., Miller, Alita A., ODonnell, John P., Wu, Xiaoyun, Sylvester, Mark A., Guler, Satenig, Iyer, Ramkumar, Shapiro, Adam B., Carter, Nicole M., Velez-Vega, Camilo, Moussa, Samir H., McLeod, Sarah M., Chen, April, Tanudra, Angela M., Zhang, Jing, Comita-Prevoir, Janelle, Romero, Jan A., Huynh, Hoan, Ferguson, Andrew D., Horanyi, Peter S., Mayclin, Stephen J., Heine, Henry S., Drusano, George L., Cummings, Jason E., Slayden, Richard A., Tommasi, Ruben A.

Issue&Volume: 2021-09-15

Abstract: The development of new antibiotics to treat infections caused by drug-resistant Gram-negative pathogens is of paramount importance as antibiotic resistance continues to increase worldwide1. Here we describe a strategy for the rational design of diazabicyclooctane inhibitors of penicillin-binding proteins from Gram-negative bacteria to overcome multiple mechanisms of resistance, including β-lactamase enzymes, stringent response and outer membrane permeation. Diazabicyclooctane inhibitors retain activity in the presence of β-lactamases, the primary resistance mechanism associated with β-lactam therapy in Gram-negative bacteria2,3. Although the target spectrum of an initial lead was successfully re-engineered to gain in vivo efficacy, its ability to permeate across bacterial outer membranes was insufficient for further development. Notably, the features that enhanced target potency were found to preclude compound uptake. An improved optimization strategy leveraged porin permeation properties concomitant with biochemical potency in the lead-optimization stage. This resulted in ETX0462, which has potent in vitro and in vivo activity against Pseudomonas aeruginosa plus all other Gram-negative ESKAPE pathogens, Stenotrophomonas maltophilia and biothreat pathogens. These attributes, along with a favourable preclinical safety profile, hold promise for the successful clinical development of the first novel Gram-negative chemotype to treat life-threatening antibiotic-resistant infections in more than 25 years.

DOI: 10.1038/s41586-021-03899-0

Source: https://www.nature.com/articles/s41586-021-03899-0