BrevicidineB, a New Member of the Brevicidine Family, Displays an Extended Target Specificity

Abstract

Graphical AbstractThe antimicrobial mode of action of brevicidines. Brevicidines are potent antimicrobial cyclic lipopeptides active against Gram-negative pathogens. They have low hemolytic activity and cytotoxicity. BrevicidineB, a single amino acid residue mutant of brevicidine, displays an altered antimicrobial spectrum, showing also antimicrobial activity against Gram-positive pathogens. Due to disruption of the proton motive force of Gram-negative pathogens, brevicidines act as bactericidal antibiotics. In addition, brevicidineB acts as a bactericidal antibiotic against Gram-positive pathogens, because of its disruption capacity of the cellular membrane.

Synthesis, Structure–Activity Relationship Study, Bioactivity, and Nephrotoxicity Evaluation of the Proposed Structure of the Cyclic Lipodepsipeptide Brevicidine B

“…Of note, all testing conditions were performed uniformly, employing identical MIC testing protocols and cation-adjusted MHB media, consistent with the methodology described in the original published data. 18 Analysis of the spectroscopic data for synthetic compound 2 confirmed its correct structural assignment, agreeing with the reported structure of the isolated natural compound. Consequently, the discrepancy between the reported anti-Gram-positive activity of isolated and synthetic 2 posed uncertainties regarding the accuracy of the reported structure.…”

“…The antibacterial activity of our synthetic 2 was then assessed using a standard microbroth dilution assay to establish minimum inhibitory concentration (MIC) values against a panel of Gram-negative ( E. coli , P. aeruginosa , K. pneumoniae , and A. baumannii ) and Gram-positive ( Enterococcus faecalis , S. aureus , and methicillin-resistant S. aureus (MRSA)) bacteria, including mcr-1- positive MDR E. coli strain MS8345 and the pandrug-resistant K. pneumoniae strain MS6671, closely mirroring the strains previously tested by Kuipers et al (Table ). Brevicidine ( 1 ) was also prepared using our original synthesis as a reference compound for these evaluations .…”

“…16 Pleasingly, synthetic brevicidine B (2) displayed antimicrobial activity toward the Gram-negative strains, with MIC values of 4−16 μg mL −1 (Table 1), in good agreement with the isolated compound. 18 Surprisingly however, it was inactive toward all of the Gram-positive strains tested (Table 1), with no detectable growth inhibition at the highest test concentration of 32 μgmL −1 . To establish if the discrepancy in the reported data was strain specific, synthetic 2 was subjected to testing against three further strains of MRSA (Table 2).…”

“…16,17 Brevicidine B (2), which is reported to contain a single substitution from D-Tyr 2 to D-Phe 2 in the exocyclic linear segment of 1, was recently discovered from the same strain of bacteria as 1 by the Kuipers group. 18 Surprisingly, this single amino acid change affords 2 a broader spectrum of antimicrobial activity, in that it exhibits potent activity toward both Gram-negative (MIC = 2−4 μgmL −1 ) and Gram-positive (MIC = 2−8 μgmL −1 ) pathogens. The D-Phe 2 mutation renders the N-terminal moiety of 2 more hydrophobic than 1, which in turn is hypothesized to enable it to disrupt the cell membrane of Gram-positive bacteria.…”

Bacterial proton motive force as an unprecedented target to control antimicrobial resistance

“…This phenomenon enables PMF to be exquisitely susceptible to a series of perturbances, rendering them fatal for bacteria. 73 Collectively, we highlight the significance of ΔΨ and ΔpH in all bacterial activities, leading to the possibility of discovering previously unknown compounds as new antimicrobial agents.…”