In vitro and in vivo activity profiles of broad-spectrum bacterial ATP synthase inhibitors
Bibliographic record
Abstract
Tomatidine (TO), a natural steroidal alkaloid derived from Solanaceae (e.g., tomato), is recognized for its narrow-spectrum antibiotic activity, particularly against persistent forms of Staphylococcus aureus, such as small-colony variants (SCVs). Previous studies have shown that TO exerts its effect by inhibiting S. aureus ATP synthase. In earlier work, we synthesized nearly 100 TO analogs featuring an ethylenediamine linker branched with aromatic substituents at the C3 position, and demonstrated that several of these analogs possess notable antibacterial activity against typical (non-SCV) S. aureus strains, including methicillin-resistant S. aureus (MRSA), with minimum inhibitory concentrations (MICs) ranging from 1 to 4 μg/mL. Among these, analogs incorporating an indole (TM-247) or para-substituted aryl moiety (TM-184, -I; TM-218, -Br; TM-220, -Cl; TM-303, -CF₃) emerged as lead candidates, exhibiting potent antibacterial activity in vitro against both Gram-positive and Gram-negative bacteria, including S. aureus SCVs. In the present study, we conducted a comprehensive antibacterial profiling of this compound series, including the predecessor compound TM-02, against a panel comprising 16 Gram-positive strains, 16 antibiotic-resistant Escherichia coli isolates, and two multidrug-resistant Acinetobacter baumannii strains. TM-184 emerged as the most promising candidate and was subsequently subjected to an expanded in vitro evaluation across 24 clinically relevant Gram-negative bacterial species. Furthermore, TM-184 was assessed in vivo using a neutropenic mouse thigh infection model against E. coli, demonstrating significant efficacy and resulting in a substantial reduction in bacterial burden.
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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".