Improving the Activity and Selectivity of a Scorpion-Derived Peptide, A3a, against <i>Acinetobacter baumannii</i> through Rational Design
Bibliographic record
Abstract
High Resolution Image Download MS PowerPoint Slide The rise in antimicrobial resistance has led to an increased desire to understand how antimicrobial peptides (AMPs) can be better engineered to kill antibiotic-resistant bacteria. Previously, we showed that C-terminal amidation of a peptide, identified in scorpion Androctonus amoreuxi venom, increased its activity against both Gram-positive and -negative bacteria. Here, we incorporate all-atom molecular dynamics (MD) simulations in a rational design strategy to create analogues of A3a with greater therapeutic potential. We discover two novel AMPs which achieve greater potency against, and selectivity toward, Acinetobacter baumannii ATCC 19606 but via two distinct mechanisms and which are effective in Galleria mellonella models of A. baumannii burn wound infection. While CD spectroscopy indicates A3a adopts an α-helix conformation in the presence of models of the Gram-negative bacterial plasma membrane, MD simulations reveal it adopts a hairpin conformation during initial binding. Three different strategies, designed to stabilize this hairpin conformation, produce substantially different outcomes. Deletion of Ile6 and Ile10 restricts conformational flexibility, characteristic of A3a, during membrane binding, prevents adoption of the α-helix conformation in the steady state, and abrogates the antibacterial activity. In contrast, substitution of arginine 7 to lysine (A3a[R7K]) or isoleucine 14 to tryptophan (A3a[I14W]) does not consistently affect peptide conformations. Both of these new analogues are rapidly bactericidal toward A. baumannii ATCC 19606 but A3a[R7K] also causes rapid permeabilization and while the antibacterial potency and selectivity are increased for both peptides, this is greatest for A3a[I14W]. Integration of atomistic MD simulations into a multidisciplinary approach to understanding antimicrobial peptide mechanism of action is a valuable tool for interpreting the effects of rational design strategies.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".