Mensa Bruk, Howell Gabriella L, Scott Richard, DeGrado William F
Department of Pharmaceutical Chemistry and the Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA.
PolyMedix Inc., Radnor, Pennsylvania, USA.
Antimicrob Agents Chemother. 2014 Sep;58(9):5136-45. doi: 10.1128/AAC.02955-14. Epub 2014 Jun 16.
Brilacidin (PMX30063) has shown potent bactericidal activity against drug-resistant and -susceptible strains of multiple Gram-negative and Gram-positive pathogens. In this study, we demonstrate that brilacidin causes membrane depolarization in the Gram-positive bacterium Staphylococcus aureus, to an extent comparable to that caused by the lipopeptidic drug daptomycin. Transcriptional profiling of Staphylococcus aureus by deep sequencing shows that the global response to brilacidin treatment is well correlated to those of treatment with daptomycin and the cationic antimicrobial peptide LL37 and mostly indicates abrogation of cell wall and membrane functions. Furthermore, the upregulation of various chaperones and proteases by brilacidin and daptomycin indicates that cytoplasmic protein misfolding stress may be a contributor to the mechanism of action of these drugs. These stress responses were orchestrated mainly by three two-component systems, GraSR, VraSR, and NsaSR, which have been implicated in virulence and drug resistance against other clinically available antibiotics.
布里拉西丁（PMX30063）已显示出对多种革兰氏阴性和革兰氏阳性病原体的耐药菌株及敏感菌株具有强大的杀菌活性。在本研究中，我们证明布里拉西丁可导致革兰氏阳性菌金黄色葡萄球菌的膜去极化，其程度与脂肽类药物达托霉素所引起的相当。通过深度测序对金黄色葡萄球菌进行转录谱分析表明，对布里拉西丁治疗的整体反应与达托霉素和阳离子抗菌肽LL37治疗的反应高度相关，且大多表明细胞壁和膜功能被破坏。此外，布里拉西丁和达托霉素对各种伴侣蛋白和蛋白酶的上调表明，细胞质蛋白错误折叠应激可能是这些药物作用机制的一个促成因素。这些应激反应主要由三个双组分系统GraSR、VraSR和NsaSR协调，它们与毒力及对其他临床可用抗生素的耐药性有关。
