Normandie Université, UNICAEN, U2RM, Caen, France.
Normandie Université, Laboratoire de Chimie Moléculaire et Thioorganique UMR 6507, ENSICAEN, UNICAEN, CNRS, 6 Bd du Maréchal Juin, Caen, France.
J Antimicrob Chemother. 2019 Nov 1;74(11):3162-3169. doi: 10.1093/jac/dkz322.
Enterococci intrinsically resistant to cephalosporins represent a major cause of healthcare-associated infections, and the emergence of MDR makes therapeutic approaches particularly challenging.
Teichoic acids are cell wall glycopolymers present in Gram-positive bacteria. Teichoic acids can be modified by d-alanylation, which requires four proteins encoded by the dltABCD operon. Our objective was to evaluate the Dlt system as a druggable target to treat enterococcal infections.
The susceptibility of a d-alanylation-deficient strain of Enterococcus faecalis to β-lactam antibiotics individually and/or in combination was analysed. Moreover, a DltA inhibitor was synthesized to test pharmacological inhibition of d-alanylation in vivo and in host using the animal model Galleria mellonella with different clinical isolates of E. faecalis and Enterococcus faecium.
Most cephalosporins used as mono treatment had no impact on survival of the parental strain, but were slightly lethal for the dltA mutant of E. faecalis. Addition of a very low concentration of amoxicillin significantly increased killing of the dltA mutant under these conditions. The most spectacular effect was obtained with a combination of cefotaxime (1 mg/L) and amoxicillin (0.03 mg/L). In the presence of the inhibitor, the WT strain was as susceptible to this combination treatment as the dltA mutant. This molecule associated with the antibiotics was also effective in killing other E. faecalis clinical isolates and successfully prevented death of Galleria infected with either E. faecalis or E. faecium.
The combined results support the potential usefulness of the Dlt system as a target to potentiate antibiotic combination therapies for the treatment of drug-resistant enterococci.
固有耐头孢菌素的肠球菌是医疗保健相关感染的主要原因，而 MDR 的出现使得治疗方法特别具有挑战性。
磷壁酸是存在于革兰氏阳性菌细胞壁中的糖聚合物。磷壁酸可以通过 d-丙氨酸化进行修饰，这需要 dltABCD 操纵子编码的四个蛋白。我们的目的是评估 Dlt 系统作为治疗肠球菌感染的可用药靶。
分析了缺乏 d-丙氨酸化的粪肠球菌突变株对β-内酰胺类抗生素单独和/或联合使用的敏感性。此外，合成了一种 DltA 抑制剂，以使用不同临床分离株的肠球菌和粪肠球菌的动物模型家蚕来测试体内和宿主的 d-丙氨酸化的药理学抑制。
大多数用作单一治疗的头孢菌素对亲本菌株的存活没有影响，但对粪肠球菌的 dltA 突变体略有致死作用。在这些条件下，添加非常低浓度的阿莫西林可显著增加对 dltA 突变体的杀伤作用。最显著的效果是头孢噻肟（1mg/L）和阿莫西林（0.03mg/L）联合使用。在抑制剂存在的情况下，WT 菌株对这种联合治疗的敏感性与 dltA 突变体相同。与抗生素结合的这种分子对其他粪肠球菌临床分离株也有效，并成功地防止了感染肠球菌或屎肠球菌的家蚕死亡。
综合结果支持 Dlt 系统作为增强抗生素联合治疗耐药肠球菌的靶标的潜在用途。
