From Worms to Drug Candidate: The Story of Odilorhabdins, a New Class of Antimicrobial Agents
From Worms to Drug Candidate: The Story of Odilorhabdins, a New Class of Antimicrobial Agents
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从蠕虫到候选药物：Odilorhabdins（一类新型抗菌药物）的故事
DOI：
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发表时间：
2019
影响因子：
5.2
通讯作者：
Maxime Gualtieri
中科院分区：
文献类型：
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作者：
Emilie Racine;Maxime Gualtieri
目前医学界面临的一个主要问题是抗生素耐药性。治疗革兰氏阴性感染的新型抗生素在过去40多年中一直没有出现。我们筛选了一组Xenorhabdus和光habdus菌株，以寻找对最具问题的多重耐药细菌有活性的新结构。这些物种是昆虫病原线虫及其生命周期的共生细菌，细菌基因组中非核糖体肽合成酶（NRPS）和聚酮合成酶（PKS）基因的丰富性，以及它们产生具有多种化学结构的次级代谢物的倾向，使它们成为开始雄心勃勃的药物发现计划的良好起点。Odilorhabdins （ODLs）是一种新型抗菌物质。这些化合物通过与小核糖体亚基结合来抑制细菌翻译，而当前的抗生素没有利用这些亚基。随着这类多肽的全合成的发展，一个药物化学项目开始优化它们的药理特性。NOSO-502是首个ODL临床前候选药物。该化合物目前正处于临床前开发阶段，用于治疗住院患者的多重耐药革兰氏阴性感染。
A major issue currently facing medicine is antibiotic resistance. No new class of antibiotics for the treatment of Gram-negative infections has been introduced in more than 40 years. We screened a collection of Xenorhabdus and Photorhabdus strains in the quest to discover new structures that are active against the most problematic multidrug-resistant bacteria. These species are symbiotic bacteria of entomopathogenic nematodes and their life cycle, the richness of the bacteria’s genome in non-ribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) genes, and their propensity to produce secondary metabolites with a large diversity of chemical structures make them a good starting point to begin an ambitious drug discovery program. Odilorhabdins (ODLs), a novel antibacterial class, were identified from this campaign. These compounds inhibit bacterial translation by binding to the small ribosomal subunit at a site not exploited by current antibiotics. Following the development of the total synthesis of this family of peptides, a medicinal chemistry program was started to optimize their pharmacological properties. NOSO-502, the first ODL preclinical candidate was selected. This compound is currently under preclinical development for the treatment of multidrug-resistant Gram-negative infections in hospitalized patients.
影响因子：
3.2
作者：
Haenchen, Anne;Rausch, Saskia;Suessmuth, Roderich D.
通讯作者：
Suessmuth, Roderich D.
影响因子：
64.8
作者：
Ling LL;Schneider T;Peoples AJ;Spoering AL;Engels I;Conlon BP;Mueller A;Schäberle TF;Hughes DE;Epstein S;Jones M;Lazarides L;Steadman VA;Cohen DR;Felix CR;Fetterman KA;Millett WP;Nitti AG;Zullo AM;Chen C;Lewis K
通讯作者：
Lewis K
影响因子：
8.8
作者：
Bulkley D;Brandi L;Polikanov YS;Fabbretti A;O'Connor M;Gualerzi CO;Steitz TA
通讯作者：
Steitz TA