Nosopharm, Nîmes, France.
Emerging Antibiotic Resistance Unit, National Reference Center for Emerging Antibiotic Resistance, INSERM European Unit (LEA Paris, IAME, France), University of Fribourg, Fribourg, Switzerland.
Antimicrob Agents Chemother. 2018 Aug 27;62(9). doi: 10.1128/AAC.01016-18. Print 2018 Sep.
Antibacterial activity screening of a collection of strains led to the discovery of the odilorhabdins, a new antibiotic class with broad-spectrum activity against Gram-positive and Gram-negative pathogens. Odilorhabdins inhibit bacterial translation by a new mechanism of action on ribosomes. A lead optimization program identified NOSO-502 as a promising candidate. NOSO-502 has MIC values ranging from 0.5 to 4 μg/ml against standard strains and carbapenem-resistant (CRE) isolates that produce KPC, AmpC, or OXA enzymes and metallo-β-lactamases. In addition, this compound overcomes multiple chromosome-encoded or plasmid-mediated resistance mechanisms of acquired resistance to colistin. It is effective in mouse systemic infection models against EN122 (extended-spectrum β-lactamase [ESBL]) or ATCC BAA-2469 (NDM-1), achieving a 50% effective dose (ED) of 3.5 mg/kg of body weight and 1-, 2-, and 3-log reductions in blood burden at 2.6, 3.8, and 5.9 mg/kg, respectively, in the first model and 100% survival in the second, starting with a dose as low as 4 mg/kg. In a urinary tract infection (UTI) model with UTI89, urine, bladder, and kidney burdens were reduced by 2.39, 1.96, and 1.36 log CFU/ml, respectively, after injection of 24 mg/kg. There was no cytotoxicity against HepG2, HK-2, or human renal proximal tubular epithelial cells (HRPTEpiC), no inhibition of hERG-CHO or Nav 1.5-HEK current, and no increase of micronuclei at 512 μM. NOSO-502, a compound with a new mechanism of action, is active against , including all classes of CRE, has a low potential for resistance development, shows efficacy in several mouse models, and has a favorable safety profile.
对一系列菌株进行的抗菌活性筛选导致了奥多利哈丁（odilorhabdins）的发现，这是一种具有针对革兰氏阳性和革兰氏阴性病原体的广谱活性的新型抗生素类别。奥多利哈丁通过核糖体的新作用机制抑制细菌翻译。一个先导优化项目确定 NOSO-502 是一种很有前途的候选药物。NOSO-502 对标准菌株和产生 KPC、AmpC 或 OXA 酶和金属β-内酰胺酶的碳青霉烯类耐药 （CRE） 分离株的 MIC 值范围为 0.5 至 4μg/ml。此外，该化合物克服了对多粘菌素获得性耐药的多种染色体编码或质粒介导的耐药机制。它在针对 EN122（扩展谱β-内酰胺酶 [ESBL]）或 ATCC BAA-2469（NDM-1）的小鼠全身感染模型中有效，实现了 50%有效剂量（ED）为 3.5mg/kg 体重，在第一个模型中，血液负荷分别减少 2 对数、3 对数和 4 对数，在 2.6、3.8 和 5.9mg/kg 时，在第二个模型中，起始剂量低至 4mg/kg 时，100%存活。在与 UTI89 的尿路感染（UTI）模型中，注射 24mg/kg 后，尿液、膀胱和肾脏的负荷分别减少了 2.39、1.96 和 1.36 对数 CFU/ml。该化合物对 HepG2、HK-2 或人肾近端小管上皮细胞（HRPTEpiC）没有细胞毒性，对 hERG-CHO 或 Nav 1.5-HEK 电流没有抑制作用，在 512μM 时也没有增加微核。NOSO-502 是一种具有新作用机制的化合物，对 具有活性，包括所有类别的 CRE，具有低耐药潜力，在几种小鼠模型中显示出疗效，并具有良好的安全性。
