Lab for Sustainable Antimicrobials, Department of Pharmacy, Sichuan Agricultural University, Chengdu, China.
Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands.
Antimicrob Agents Chemother. 2023 May 17;67(5):e0001023. doi: 10.1128/aac.00010-23. Epub 2023 Mar 13.
Due to the accelerated appearance of antimicrobial-resistant (AMR) pathogens in clinical infections, new first-in-class antibiotics, operating via novel modes of action, are desperately needed. Brevicidine, a bacterial nonribosomally produced cyclic lipopeptide, has shown potent and selective antimicrobial activity against Gram-negative pathogens. However, before our investigations, little was known about how brevicidine exerts its potent bactericidal effect against Gram-negative pathogens. In this study, we find that brevicidine has potent antimicrobial activity against AMR pathogens, with MIC values ranging between 0.5 μM (0.8 mg/L) and 2 μM (3.0 mg/L). In addition, brevicidine showed potent antibiofilm activity against the pathogens, with the same 100% inhibition and 100% eradication concentration of 4 μM (6.1 mg/L). Further mechanistic studies showed that brevicidine exerts its potent bactericidal activity by interacting with lipopolysaccharide in the outer membrane, targeting phosphatidylglycerol and cardiolipin in the inner membrane, and dissipating the proton motive force of bacteria. This results in metabolic perturbation, including the inhibition of ATP synthesis; the inhibition of the dehydrogenation of NADH; the accumulation of reactive oxygen species in bacteria; and the inhibition of protein synthesis. Finally, brevicidine showed a good therapeutic effect in a mouse peritonitis-sepsis model. Our findings pave the way for further research on the clinical applications of brevicidine to combat prevalent infections caused by AMR Gram-negative pathogens worldwide.
由于临床感染中出现了抗微生物药物耐药（AMR）病原体的加速出现，因此迫切需要新型的、作用机制新颖的首创抗生素。布雷维丁是一种细菌非核糖体产生的环状脂肽，对革兰氏阴性病原体具有强大而选择性的抗菌活性。然而，在我们的研究之前，人们对布雷维丁如何发挥其对革兰氏阴性病原体的强大杀菌作用知之甚少。在这项研究中，我们发现布雷维丁对 AMR 病原体具有强大的抗菌活性，MIC 值在 0.5 μM（0.8 mg/L）至 2 μM（3.0 mg/L）之间。此外，布雷维丁对病原体表现出强大的抗生物膜活性，相同的 100%抑制和 100%清除浓度为 4 μM（6.1 mg/L）。进一步的机制研究表明，布雷维丁通过与外膜中的脂多糖相互作用，靶向内膜中的磷脂酰甘油和心磷脂，以及耗散细菌的质子动力势，发挥其强大的杀菌活性。这导致代谢紊乱，包括 ATP 合成的抑制；NADH 脱氢的抑制；细菌中活性氧物质的积累；以及蛋白质合成的抑制。最后，布雷维丁在小鼠腹膜炎-败血症模型中显示出良好的治疗效果。我们的研究结果为进一步研究布雷维丁在临床上用于对抗全球流行的由 AMR 革兰氏阴性病原体引起的感染铺平了道路。
