Exploring the structure-activity relationship of brevibacillin: Discovery of synthetic analogues with an extended spectrum of activity
Bibliographic record
Abstract
Brevibacillin is an antimicrobial lipopeptide produced by Brevibacillus laterosporus with promising activity against several clinically relevant Gram-positive pathogens, including antibiotic-resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). Herein, we describe the optimization of the synthetic approach to produce brevibacillin and new analogues as well as a structure-activity relationship investigation to increase the activity, modify the spectrum of action and reduce the cytotoxicity. The alanine-scan of the lipopeptide revealed that cationic amino acids are essential for its activity against Gram-negative strains while the overall hydrophobicity plays an important role in the inhibition of Gram-positive bacteria and hemolysis. Substitution of the N-terminal acyl chain with fatty acids of different length yielded equipotent analogues but enhanced the hemolytic activity compared to brevibacillin. In another series of analogues, the introduction of a cationic amino acid at position 1 increased the inhibitory activity toward Gram-negative bacteria and significantly reduced the hemolytic activity, but at the cost of less potency against Gram-positive strains. Finally, the combination of both N-acyl and position 1 substitutions resulted in analogues exhibiting an extended spectrum of activity with minimal inhibitory concentration values in the low micromolar range against Gram-positive S. aureus, MRSA, Bacillus subtilis, Enterococcus faecium and Gram-negative Escherichia coli, Salmonella enterica, Klebsiella pneumoniae and Acinetobacter baumannii as well as enhanced killing kinetics compared to brevibacillin. With their enhanced synthetic accessibility, strong inhibitory activity, shifted or extended spectrum of action and improved selectivity index towards Gram-negative bacteria, these brevibacillin analogues are promising candidates for the development of new antimicrobials.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".