Racine Emilie, Gualtieri Maxime
Nosopharm, Nîmes, France.
Front Microbiol. 2019 Dec 18;10:2893. doi: 10.3389/fmicb.2019.02893. eCollection 2019.
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 and 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.
医学目前面临的一个主要问题是抗生素耐药性。40多年来，尚未推出用于治疗革兰氏阴性菌感染的新型抗生素类别。我们筛选了一系列菌株，以发现对最具问题的多重耐药细菌具有活性的新结构。这些物种是昆虫病原线虫的共生细菌，它们的生命周期、细菌基因组中非核糖体肽合成酶（NRPS）和聚酮合酶（PKS）基因的丰富性，以及它们产生具有多种化学结构的次生代谢物的倾向，使它们成为启动一项雄心勃勃的药物发现计划的良好起点。从这项研究中鉴定出了一类新型抗菌物质——杀线虫素（ODLs）。这些化合物通过结合到小核糖体亚基上一个当前抗生素未利用的位点来抑制细菌翻译。在完成该肽家族的全合成开发后，启动了一个药物化学项目来优化它们的药理特性。首个ODL临床前候选药物NOSO-502被选定。该化合物目前正在进行临床前开发，用于治疗住院患者的多重耐药革兰氏阴性菌感染。
