Many bacterial illnesses have become more challenging, or perhaps impossible, to treat with traditional antimicrobials as a result of the increased emergence of antimicrobial resistance (AMR) in bacterial pathogens. Despite the urgency of the AMR crisis, fewer novel antimicrobials have been licensed over the past 20 years, particularly those used to treat infections caused by Gram-negative pathogens. Numerous therapeutically recognized antibacterial cyclic non-ribosomally generated peptides (NRP) are created by bacteria. One of them is Brevicidine (Bre), a bacterial non-ribosomally produced cyclic lipopeptide which contains 12 amino acids with a 4-Methyl-Hexanoyl chain at its N-terminal and a lactone bond joining Thr9 to Ser12. Brevicidine was first isolated from the Brevibacillus laterosporus DSM25 in 2018, it also has a unique synthetic route which makes it more attractive for the production of antimicrobials.
Multi-Drug Resistant Bacteria. Image Courtesy of Dr Graham Beards
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Brevicidine is a very distinctive drug
Brevicidine operates in a very peculiar manner. Gram-negative bacteria are particularly susceptible to the antimicrobial effects of Brevicidine including Escherichia coli, Klebsiella pneumonia, and Pseudomonas Aeruginosa. In a prior investigation, it was discovered that Brevicidine reduced the proton motive force of bacteria. A study was carried out to investigate how exactly Brevicidine kills Gram-negative microorganisms at the molecular level. Additionally, the antibacterial efficacy against AMR Enterobacteriaceae, the anti-biofilm activity against E. coli, and the in vivo therapeutic impact of Brevicidine were also looked at.
A minimum inhibitory concentration(MIC) assay was used to determine the antibacterial activity of Brevicidine against AMR Enterobacteriaceae pathogens. Brevicidine’s anti-biofilm activity against E. coli was assessed. In addition, fluorescent probes were used to examine how Brevicidine affected the integrity of the membranes of Gram-negative bacteria. The findings demonstrated that Brevicidine disrupts the proton motive force of Gram-negative pathogens by interacting with lipopolysaccharide (LPS) in the outer membrane as well as phosphatidylglycerol (PG) and cardiolipin (CL) in the inner membrane. This results in the suppression of adenosine triphosphate (ATP) synthesis, the buildup of reactive oxygen species (ROS) and nicotinamide adenine dinucleotide (NADH), and the death of bacteria. Additionally, Brevicidine displayed strong antimicrobial activity against AMR Gram-negative pathogens as well as effective anti-biofilm activity against Gram-negative pathogens.
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Clinical significance
Remarkably, Brevicidine demonstrated an excellent therapeutic effect in a mouse model of E. coli-induced peritonitis and sepsis. These findings will open the door to more investigations into brevicidine’s clinical application which can be used to fight the widespread infections brought on by AMR Gram-negative pathogens in all countries.
Conclusion
AMR is a serious threat to human health globally. With conventional antimicrobials, treating many bacterial infections has grown more challenging, if not impossible. Therefore, there is a dire need for fresh, first-in-class antibiotics with new mechanisms of action. Fortunately, it was shown that Brevicidine has a strong antimicrobial effect against Enterobacteriaceae pathogens.
