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Nature:药物联合制剂有望抵御抗生素耐药性

发布日期:2018-07-17来源:热心肠日报发布人:梦缘徽州

原标题:抗菌药联合制剂的菌种特异性活性

① 通过检测79种抗生素、药物和食品添加剂等化合物近3000种不同剂量的联合制剂的抗菌作用,阐释药物间相互作用模式;

② 70%以上的药物间互作具有菌种特异性,20%表现出菌株特异性,说明联合制剂具有进行窄谱治疗的巨大潜能;

③ 拮抗作用比协同作用更普遍,拮抗几乎仅发生于胞内靶向不同的药物间,协同更保守且多见于胞内靶向相同的药物间;

④ 一些药物联合制剂可有效抵御多重耐药临床分离株,并在大蜡螟感染模型中恢复多粘菌素的抗生素有效性。

Species-specific activity of antibacterial drug combinations

DOI: 10.1038/s41586-018-0278-9

Abstract:
The spread of antimicrobial resistance has become a serious public health concern, making once-treatable diseases deadly again and undermining the achievements of modern medicine. Drug combinations can help to fight multi-drug-resistant bacterial infections, yet they are largely unexplored and rarely used in clinics. Here we profile almost 3,000 dose-resolved combinations of antibiotics, human-targeted drugs and food additives in six strains from three Gram-negative pathogens-Escherichia coli, Salmonella enterica serovar Typhimurium and Pseudomonas aeruginosa-to identify general principles for antibacterial drug combinations and understand their potential. Despite the phylogenetic relatedness of the three species, more than 70% of the drug-drug interactions that we detected are species-specific and 20% display strain specificity, revealing a large potential for narrow-spectrum therapies. Overall, antagonisms are more common than synergies and occur almost exclusively between drugs that target different cellular processes, whereas synergies are more conserved and are enriched in drugs that target the same process. We provide mechanistic insights into this dichotomy and further dissect the interactions of the food additive vanillin. Finally, we demonstrate that several synergies are effective against multi-drug-resistant clinical isolates in vitro and during infections of the larvae of the greater wax moth Galleria mellonella, with one reverting resistance to the last-resort antibiotic colistin.

First Authors:
Ana Rita Brochado

Correspondence:
Athanasios Typas

All Authors:
Ana Rita Brochado,Anja Telzerow,Jacob Bobonis,Manuel Banzhaf,André Mateus,Joel Selkrig,Emily Huth,Stefan Bassler,Jordi Zamarre?o Beas,Matylda Zietek,Natalie Ng,Sunniva Foerster,Benjamin Ezraty,Béatrice Py,Frédéric Barras,Mikhail M Savitski,Peer Bork,Stephan G?ttig,Athanasios Typas

7/1/18Letter