Center for Peptide-based Antibiotics, Department of Cellular and Molecular Medicine, The Panum Institute, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
Department for Bacteria Parasites and Fungi, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen, Denmark.
ACS Infect Dis. 2021 Aug 13;7(8):2152-2163. doi: 10.1021/acsinfecdis.1c00147. Epub 2021 Jul 6.
The peptidomimetic H-[NLys-BuAla]-NH (CEP-136), which exhibits low inherent antimicrobial activity against Gram-negative bacteria (MIC = 16-64 μM), was shown to significantly potentiate the antibacterial activity of several clinically important antibiotics against the human pathogens , , , and . Thus, the antibacterial spectrum of rifampicin, clarithromycin, and azithromycin could be extended to include also these Gram-negative bacteria. Additionally, the potentiation effect was demonstrated in a panel of clinically relevant multidrug-resistant isolates including extended-spectrum β-lactamase (ESBL)- and carbapenemase-producing as well as colistin-resistant strains. For some peptidomimetic-antibiotic combinations, the strong synergy corresponded to a more than 50-fold reduction of the minimal inhibitory concentration of the antibiotic. Mechanistic studies indicate that the potentiation arises from a permeabilization effect exerted on the outer membrane lipopolysaccharide layer of the Gram-negative bacteria without significant disruption of the inner membrane. Furthermore, the peptidomimetic enhancer exhibited only a marginal effect on the viability of mammalian HepG2 cells even at concentrations 100-fold higher than that enabling the antibiotic enhancement. Also, a low hemolytic activity combined with limited acute toxicity of CEP-136 in healthy mice allowed validation of the potentiation effect on both rifampicin and azithromycin treatment in a murine peritonitis model. Thus, CEP-136 is an interesting hit compound for further development of effective adjuvants for repurposing antibiotics for use against infections by multidrug-resistant Gram-negative bacteria.
肽模拟物 H-[NLys-BuAla]-NH（CEP-136）对革兰氏阴性菌（MIC=16-64 μM）的固有抗菌活性较低，但它能显著增强几种临床重要抗生素对人类病原体的抗菌活性，如、、、和。因此，利福平、克拉霉素和阿奇霉素的抗菌谱可以扩展到包括这些革兰氏阴性菌。此外，在包括产超广谱β-内酰胺酶（ESBL）和碳青霉烯酶以及多粘菌素耐药株在内的一组临床相关多重耐药分离株中，也证明了这种增效作用。对于一些肽模拟物-抗生素组合，强烈的协同作用对应于抗生素最小抑菌浓度降低了 50 多倍。机制研究表明，这种增效作用源于对革兰氏阴性菌外膜脂多糖层的通透性作用，而对内膜没有明显的破坏。此外，即使在比增强抗生素作用的浓度高 100 倍的浓度下，肽模拟物增强剂对哺乳动物 HepG2 细胞的活力也只有轻微影响。此外，CEP-136 的低溶血活性和在健康小鼠中的有限急性毒性，使利福平和阿奇霉素治疗在腹膜炎模型中的增效作用得到验证。因此，CEP-136 是一种有趣的先导化合物，可进一步开发有效的佐剂，重新利用抗生素治疗多药耐药革兰氏阴性菌感染。
