The Calcium-Dependent Antibiotics: Structure–Activity Relationships and Determination of Their Lipid Target
Bibliographic record
Abstract
. Their target was unknown, and the mechanism of action is uncertain. Herein, we report new routes for the synthesis of CDA4b and its analogues, explore the structure-activity relationships at its lipid tail and at positions 3, 9, and 11, and determine the CDAs' lipid target. A CDA4b analogue in which the epoxide group in CDA's 6-carbon lipid was replaced with a cyclopropyl group was 4-fold more active than CDA4b which suggests that the epoxide group is not acting as an electrophile to form a covalent bond with CDA4b's target. The activity of this cyclopropyl analogue was significantly increased by extending the length of the lipid to 10 carbons. Studies with analogues in which d-HOAsn9 is replaced with d-Asn9 or d-Ser9 reveal that the hydroxy group of the d-HOAsn9 residue is not crucial for CDAs' activity, while the amide moiety is important for activity. The l-Trp residue at position 11 could be replaced with l-kynurenine (l-Kyn) without significant loss of activity, while replacing the d-Trp residue at position 3 with d-Kyn resulted in a significant loss of activity. MIC values determined in the presence and absence of exogenous phospholipids and fluorescence spectroscopy studies using natural CDAs and CDA4b analogues containing Kyn and model membranes revealed that the CDAs' primary lipid target is cardiolipin, a target that is unique among the broader class of known calcium-dependent antibiotics.
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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".