PT  - JOURNAL ARTICLE
AU  - Xinghong Zhao
AU  - Xinyi Zhong
AU  - Hongping Wan
AU  - Lu Liu
AU  - Xu Song
AU  - Yuanfeng Zou
AU  - Lixia Li
AU  - Renyong Jia
AU  - Juchun Lin
AU  - Huaqiao Tang
AU  - Gang Ye
AU  - Jianqing Yang
AU  - Shan Zhao
AU  - Yifei Lang
AU  - Zhongqiong Yin
AU  - Oscar P. Kuipers
TI  - Brevicidine, a bacterial non-ribosomally produced cyclic antimicrobial lipopeptide with a unique <em>modus operandi</em>
AID  - 10.1101/2022.10.07.511251
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.10.07.511251
4099  - http://biorxiv.org/content/early/2022/12/04/2022.10.07.511251.short
4100  - http://biorxiv.org/content/early/2022/12/04/2022.10.07.511251.full
AB  - Due to the accelerated appearance of antibiotic-resistant (AMR) pathogens in clinical infections, new first-in-class antibiotics, operating via novel modes of action, are desperately-needed. Brevicidine, a bacterial non-ribosomally 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 Enterobacteriaceae pathogens, with a MIC value ranging between 0.5μM (0.8mg/L) and 2μM (3.0mg/L). In addition, brevicidine showed potent anti-biofilm activity against the Enterobacteriaceae pathogens, with same 100% inhibition and 100% eradication concentration of 4μM (6.1mg/L). Further mechanistic studies showed that brevicidine exerts its potent bactericidal activity via 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 inhibition of adenosine triphosphate synthesis, inhibits the dehydrogenation of nicotinamide adenine dinucleotides, accumulation of reactive oxygen species in bacteria, and inhibition of protein synthesis. Lastly, brevicidine showed a good therapeutic effect in a mouse peritonitis–sepsis model. Our findings pave the way for further research on clinical applications of brevicidine, to combat the prevalent infections caused by AMR Gram-negative pathogens worldwide.Competing Interest StatementThe authors have declared no competing interest.