Mishra Nigam M, Stolarzewicz Izabela, Cannaerts David, Schuermans Joris, Lavigne Rob, Looz Yannick, Landuyt Bart, Schoofs Liliane, Schols Dominique, Paeshuyse Jan, Hickenbotham Peter, Clokie Martha, Luyten Walter, Van der Eycken Erik V, Briers Yves
Laboratory for Organic and Microwave-Assisted Chemistry, Department of Chemistry, KU Leuven, Leuven, Belgium.
Department of Chemistry, Warsaw University of Life Sciences, Warsaw, Poland.
Front Microbiol. 2018 Jun 7;9:1175. doi: 10.3389/fmicb.2018.01175. eCollection 2018.
Vancomycin is a glycopeptide antibiotic that inhibits transpeptidation during cell wall synthesis by binding to the D-Ala-D-Ala termini of lipid II. For long, it has been used as a last resort antibiotic. However, since the emergence of the first vancomycin-resistant enterococci in 1987, vancomycin resistance has become widespread, especially in hospitals. We have synthesized and evaluated 110 vancomycin analogs modified at the C-terminal carboxyl group of the heptapeptide moiety with RNHRNH substituents. Through iterative optimizations of the substituents, we identified vancomycin analogs that fully restore (or even exceed) the original inhibitory activity against vancomycin-resistant enterococci (VRE), vancomycin-intermediate (VISA) and vancomycin-resistant (VRSA) strains. The best analogs have improved growth inhibitory activity and therapeutic indices against a broad set of VRE and methicillin-resistant (MRSA) isolates. They also exceed the activity of vancomycin against ribotypes. Vanc-39 and Vanc-42 have a low probability to provoke antibiotic resistance, and overcome different vancomycin resistance mechanisms (VanA, VanB, and VanC1).
万古霉素是一种糖肽类抗生素，它通过与脂联素II的D-丙氨酰-D-丙氨酸末端结合来抑制细胞壁合成过程中的转肽作用。长期以来，它一直被用作最后一线抗生素。然而，自1987年首次出现耐万古霉素肠球菌以来，万古霉素耐药性已广泛传播，尤其是在医院。我们合成并评估了110种在七肽部分的C端羧基处用RNHRNH取代基修饰的万古霉素类似物。通过对取代基的迭代优化，我们鉴定出了对耐万古霉素肠球菌（VRE）、万古霉素中介（VISA）和耐万古霉素金黄色葡萄球菌（VRSA）菌株完全恢复（甚至超过）原始抑制活性的万古霉素类似物。最佳类似物对多种VRE和耐甲氧西林金黄色葡萄球菌（MRSA）分离株具有改善的生长抑制活性和治疗指数。它们还超过了万古霉素对不同核糖型的活性。Vanc-39和Vanc-42引发抗生素耐药性的可能性较低，并克服了不同的万古霉素耐药机制（VanA、VanB和VanC1）。
