Chu John, Vila-Farres Xavier, Inoyama Daigo, Gallardo-Macias Ricardo, Jaskowski Mark, Satish Shruthi, Freundlich Joel S, Brady Sean F
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University , 1230 York Avenue, New York, New York 10065, United States.
Department of Pharmacology, Physiology, and Neuroscience, Rutgers University-New Jersey Medical School , 185 South Orange Avenue, Newark, New Jersey 07103, United States.
ACS Infect Dis. 2018 Jan 12;4(1):33-38. doi: 10.1021/acsinfecdis.7b00056. Epub 2017 Sep 11.
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.
翻转酶MurJ负责将细胞壁中间产物脂质II从细胞质转运到细胞外。虽然它对细菌的生存至关重要，但仍是抗菌治疗中未得到充分利用的靶点。腐霉素类抗生素是脂质II翻转酶（MurJ）抑制剂，是根据从人类微生物组中发现的次级代谢物基因簇得出的生物信息学预测合成的。在此，我们描述了围绕腐霉素A开展的一项构效关系研究，该研究产生了腐霉素17S。与腐霉素A相比，17S是一种更强效的β-内酰胺增强剂，具有更广泛的活性谱，现在包括耐甲氧西林金黄色葡萄球菌（MRSA）和耐万古霉素粪肠球菌（VRE），并且与β-内酰胺联合使用时不会产生任何可检测到的耐药性。β-内酰胺与腐霉素17S的组合提供了一种潜在有用的长期抗MRSA治疗方案。
