Discovery of broad-spectrum bacterial polyamine detoxification inhibitors as potential antivirulence agents and antibiotic adjuvants
Bibliographic record
Abstract
Abstract The alarming rise in antimicrobial resistance reinforces an urgent need for new antimicrobial strategies. Chemicals at infection sites, such as polyamines, often influence microbial virulence and antibiotic response. Polyamines are cationic small molecules overproduced by the host during infection, modulating immune responses—the ability of several pathogens to detoxify polyamines correlated with hypervirulence. We sought to uncover inhibitors of polyamine detoxification through a high-throughput whole-cell screen against the community-acquired methicillin-resistant Staphylococcus aureus USA300, identifying the polyamine analog OES2-0017. This inhibitor synergized with polyamines at the low micromolar range, inhibiting a polyamine detoxification spermine/spermidine acetyltransferase SSAT (SpeG) and another previously uncharacterized S. aureus SSAT (denoted PaiA Sa herein). OES2-0017 showed growth-inhibitory effects at higher concentrations, perturbing the bacterial membrane with no detectable effects against eukaryotic membranes at the same concentration range. OES2-0017 showed similar broad-spectrum activities against various Gram-positive and Gram-negative pathogens. OES2-0017 abolished the polyamine-mediated resistance to antibiotics, including vancomycin, in MRSA USA300, phenocopying the Δ speG mutant and suggesting its potential utility as an antibiotic adjuvant. OES2-0017 eradicated SpeG-expressing Salmonella Typhimurium inside murine macrophages, suggesting its potential as an antivirulence agent. Small-scale structure-activity relationship, eukaryotic toxicity, and enzymatic inhibition against the human SSAT (SAT1) assays identified analogs with higher bacterial enzyme specificity and no toxicity at the antimicrobial range. Our screen also uncovered additional inhibitors, including the catechol derivative isoproterenol (OES1-1087), showing a similar mode of action and activity as OES2-0017 but with lower potency. This study provides novel antimicrobial compounds with broad-spectrum activity and a novel mode of action for multidrug-resistant priority pathogens.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
| 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".