The Cell Envelope Stress Response of Bacillus subtilis towards Laspartomycin C.
The Cell Envelope Stress Response of Bacillus subtilis towards Laspartomycin C.
复制标题
DOI：
10.3390/antibiotics9110729
复制
发表时间：
2020-10-23
期刊：
影响因子：
--
通讯作者：
Fritz G
中科院分区：
文献类型：
--
作者：
Diehl A;Wood TM;Gebhard S;Martin NI;Fritz G
细胞壁抗生素是我们对抗革兰氏阳性病原体的重要工具，但许多菌株对现有药物的耐药性越来越强。衣康霉素C是一种新型抗生素，其靶向磷酸十一异戊二烯酯（UP），这是细胞壁生物合成的脂质II循环中的关键中间体。虽然已经对伊曲霉素C进行了彻底的生物化学研究，但对细菌中潜在的耐药机制缺乏详细的了解。在这里，我们使用报告菌株来监测在枯草芽孢杆菌细胞包膜应激反应网络中的中心抗性模块的活性，并使用敲除菌株来确定对这些模块的抗性的影响。与仅激活ECF σ因子控制的应激反应模块的密切相关的UP结合抗生素弗鲁利米星B相反，我们发现衣康霉素C另外触发对膜扰动和其他脂质II循环中间体的阻断反应的应激反应系统的激活。有趣的是，所研究的耐药基因中没有一个对伊曲霉素C具有任何保护作用。虽然这对于阿斯巴甜霉素C的治疗用途似乎很有希望，但它引起了人们的担忧，即现有的细胞被膜应激反应网络可能已经准备好在长期或重复接触这种新抗生素期间自发产生耐药性。
Cell wall antibiotics are important tools in our fight against Gram-positive pathogens, but many strains become increasingly resistant against existing drugs. Laspartomycin C is a novel antibiotic that targets undecaprenyl phosphate (UP), a key intermediate in the lipid II cycle of cell wall biosynthesis. While laspartomycin C has been thoroughly examined biochemically, detailed knowledge about potential resistance mechanisms in bacteria is lacking. Here, we use reporter strains to monitor the activity of central resistance modules in the Bacillus subtilis cell envelope stress response network during laspartomycin C attack and determine the impact on the resistance of these modules using knock-out strains. In contrast to the closely related UP-binding antibiotic friulimicin B, which only activates ECF σ factor-controlled stress response modules, we find that laspartomycin C additionally triggers activation of stress response systems reacting to membrane perturbation and blockage of other lipid II cycle intermediates. Interestingly, none of the studied resistance genes conferred any kind of protection against laspartomycin C. While this appears promising for therapeutic use of laspartomycin C, it raises concerns that existing cell envelope stress response networks may already be poised for spontaneous development of resistance during prolonged or repeated exposure to this new antibiotic.
登录
查看更多内容
影响因子：
3.6
作者：
Mascher, T;Margulis, NG;Helmann, JD
通讯作者：
Helmann, JD
影响因子：
3.2
作者：
Jordan, Sina;Junker, Anja;Mascher, Thorsten
通讯作者：
Mascher, Thorsten
影响因子：
4.9
作者：
Gebhard, Susanne;Fang, Chong;Cook, Gregory M.
通讯作者：
Cook, Gregory M.
影响因子：
3.6
作者：
Gebhard, Susanne;Mascher, Thorsten
通讯作者：
Mascher, Thorsten
影响因子：
3.3
作者：
Mescola, Andrea;Ragazzini, Gregorio;Alessandrini, Andrea
通讯作者：
Alessandrini, Andrea