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Human Microbiome Inspired Antibiotics with Improved β-Lactam Synergy against MDR Staphylococcus aureus.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2017-09-11 , DOI: 10.1021/acsinfecdis.7b00056
John Chu 1 , Xavier Vila-Farres 1 , Daigo Inoyama 2 , Ricardo Gallardo-Macias 2 , Mark Jaskowski 2 , Shruthi Satish 2 , Joel S Freundlich 2 , Sean F Brady 1
Affiliation  

The flippase MurJ is responsible for transporting the cell wall intermediate lipid II from the cytoplasm to the outside of the cell. While essential for the survival of bacteria, it remains an underexploited target for antibacterial therapy. The humimycin antibiotics are lipid II flippase (MurJ) inhibitors that were synthesized on the basis of bioinformatic predictions derived from secondary metabolite gene clusters found in the human microbiome. Here, we describe an SAR campaign around humimycin A that produced humimycin 17S. Compared to humimycin A, 17S is a more potent β-lactam potentiator, has a broader spectrum of activity, which now includes both methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus faecalis (VRE), and did not lead to any detectable resistance when used in combination with a β-lactam. Combinations of β-lactam and humimycin 17S provide a potentially useful long-term MRSA regimen.

中文翻译:

具有改善的β-内酰胺协同作用的人类微生物学启发的抗生素,可抵抗金黄色葡萄球菌。

脂酶MurJ负责将细胞壁中间脂质II从细胞质转运至细胞外部。尽管对于细菌的生存至关重要,但它仍然是抗菌治疗的未充分开发的目标。humimycin抗生素是脂质II翻转酶(MurJ)抑制剂,是根据人类微生物组中次生代谢物基因簇衍生的生物信息学预测合成的。在这里,我们描述了产生humimycin 17S的humimycin A周围的SAR运动。与Humimycin A相比,17S是更有效的β-内酰胺增效剂,具有更广泛的活性谱,目前包括耐甲氧西林的金黄色葡萄球菌(MRSA)和耐万古霉素的粪肠球菌(VRE),并且未导致任何可检测到的耐药性当与β-内酰胺结合使用时。
更新日期:2017-09-11
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