The avermectin, emamectin benzoate, kills gram-positive bacteria and targets the cell envelope of <i>Bacillus subtilis</i>
Bibliographic record
Abstract
ABSTRACT The avermectin family of anthelmintics is largely considered to lack antibacterial activity against gram-positive and gram-negative bacteria. Here, we screened six avermectins (ivermectin, eprinomectin, doramectin, abamectin, selamectin, and emamectin benzoate) and a structurally related milbemycin (moxidectin) for antibacterial activity against a panel of representative gram-positive and gram-negative bacteria. We report that emamectin benzoate exhibited activity against several species of gram-positive bacteria, whereas selamectin was active against Staphylococcus aureus and Staphylococcus epidermidis . Emamectin benzoate was the only avermectin with activity against hyper-permeabilized Escherichia coli cells. Using the model bacterium, Bacillus subtilis , we demonstrated that emamectin benzoate is bactericidal, causing rapid lysis and extensive cell envelope damage. To gather insight into its molecular target, several mutant selection methods were employed but failed to yield emamectin benzoate-resistant mutants. Macromolecular synthesis assays indicated that emamectin benzoate inhibited peptidoglycan synthesis. Transcriptome sequencing showed that emamectin benzoate activates the Lia and SigM cell envelope stress-responsive systems and induces the expression of peptidoglycan biosynthetic genes. Although the inactivation or activation of the Lia system did not alter the susceptibility of B. subtilis to emamectin benzoate, CRISPRi-mediated repression of individual essential peptidoglycan biosynthetic genes sensitized B. subtilis to emamectin benzoate. Emamectin benzoate synergized with cell wall-targeting antibiotics (nisin, fosfomycin, daptomycin, and tunicamycin) against B. subtilis . Phosphatidylglycerol antagonized the antibacterial activity of emamectin benzoate, suggesting that EMB likely interacts with membrane phospholipids to exert its effect. Altogether, avermectins exhibit anti-gram-positive activity, albeit with differing levels of potency and selectivity, and, mechanistically, emamectin benzoate targets the cell envelope. IMPORTANCE Avermectins and the structurally related milbemycins are thought to lack antibacterial activity against gram-positive and gram-negative bacteria. Using antimicrobial susceptibility testing, we showed that avermectins and the milbemycin, moxidectin, possess anti-gram-positive activity, with the avermectin, emamectin benzoate, exhibiting the greatest spectrum of activity. Using B. subtilis as a model organism, we showed that emamectin benzoate is bactericidal, causes extensive cell envelope damage, and inhibits peptidoglycan synthesis. Transcriptome analysis of B. subtilis cells treated with emamectin benzoate showed that this avermectin activates two envelope stress-responsive systems and induces the expression of peptidoglycan biosynthetic genes, likely to counteract emamectin benzoate-mediated cell envelope damage. As some avermectins and milbemycins are approved for human and animal use, these drugs may be repurposed for the treatment of gram-positive bacterial infections. Furthermore, given the extensive use of these agents in agriculture, aquaculture, and medicine, examination of their off-target effects on various bacterial communities is warranted.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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".