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Abaucin
Abaucin
Abaucin
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Abaucin
Identifiers
  • 1'-[2-[4-(trifluoromethyl)phenyl]ethyl]spiro[1H-3,1-benzoxazine-4,4'-piperidine]-2-one
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
ChEBI
ChEMBL
Chemical and physical data
FormulaC21H21F3N2O2
Molar mass390.406 g·mol−1
3D model (JSmol)
  • C1CN(CCC12C3=CC=CC=C3NC(=O)O2)CCC4=CC=C(C=C4)C(F)(F)F
  • InChI=1S/C21H21F3N2O2/c22-21(23,24)16-7-5-15(6-8-16)9-12-26-13-10-20(11-14-26)17-3-1-2-4-18(17)25-19(27)28-20/h1-8H,9-14H2,(H,25,27)
  • Key:HIDWEYPGMLIQSN-UHFFFAOYSA-N

Abaucin (RS-102895, MLJS-21001) is a spirocycle containing substituted phenethylamine that has been reported to show useful activity as a narrow-spectrum antibiotic.[1] There is evidence that it is effective against Acinetobacter baumannii, which is one of three bacterial species identified by the World Health Organization as a "critical threat" to humanity. Notably, abaucin was developed with assistance from artificial intelligence by a team led by the MIT Jameel Clinic's faculty lead for life sciences, James J. Collins, and McMaster's Jonathan Stokes.[2][3][4] Its mode of action involves inhibiting lipoprotein transport. The compound had previously been reported as an antagonist of the chemokine receptor CCR2, but the molecule's antibiotic activity was not discovered until 2023.[5][6][7][8][9]

A New York Times opinion piece by Peter Coy for Thanksgiving listed abaucin among scientific discoveries to be thankful for in 2023.[10]

See also

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References

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Abaucin

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from Grokipedia
Abaucin is a compound designed to combat infections caused by the multidrug-resistant bacterium , a notorious nosocomial pathogen responsible for severe wound, , and bloodstream infections. Discovered through a deep learning-guided screening process that evaluated approximately 7,500 small molecules, abaucin was identified by training a on bacterial growth inhibition data to predict antibacterial activity specifically against A. baumannii. Its mechanism of action involves perturbing lipoprotein trafficking in the bacterium by targeting the LolE protein, a component of the Lol system essential for outer membrane biogenesis, thereby selectively disrupting A. baumannii without broadly affecting beneficial . In vitro studies demonstrated abaucin's potent inhibition of A. baumannii growth, with minimal activity against other Gram-negative or , highlighting its narrow-spectrum profile that could reduce the risk of microbiome disruption associated with broad-spectrum antibiotics. Further validation in a model showed that abaucin effectively controlled A. baumannii infections, reducing bacterial burden and promoting comparable to or better than existing treatments. This AI-driven discovery, reported in 2023, underscores the potential of in accelerating antibiotic development amid the global crisis of , positioning abaucin as a promising for clinical translation against one of the World Health Organization's priority pathogens.

Discovery and Development

AI-Driven Identification

The discovery of abaucin as a novel candidate against was driven by a approach led by researchers from the Massachusetts Institute of Technology and Jonathan M. Stokes from , as detailed in their 2023 study published in Nature Chemical Biology. In this work, the team screened approximately 7,500 diverse molecules—sourced from patented compounds and synthetic libraries—for growth inhibition against A. baumannii to generate a labeled dataset for model training. This dataset served as the foundation for developing a model capable of predicting antibacterial activity. The model employed a architecture based on Chemprop, a framework for molecular property prediction, with molecular representations generated using RDKit to create graph-based features akin to fingerprints that capture structural information. Trained on the growth inhibition outcomes from the 7,500-molecule , the model learned to forecast the likelihood of a compound inhibiting A. baumannii growth, focusing specifically on potency against this while distinguishing it from activity against other . This targeted prediction process enabled efficient screening of larger chemical spaces without initial lab testing. Applying the trained model to the Drug Repurposing Hub library—a collection of approximately 6,000 small molecules including FDA-approved, clinical-stage, and preclinical compounds—the researchers prioritized candidates based on predicted antibacterial potency scores. , previously identified as RS-102895, emerged as the top-ranked molecule due to its exceptionally high predicted efficacy against A. baumannii, with the model suggesting interference in lipoprotein trafficking as a potential target pathway.

Validation and Initial Research

Following the AI-driven screening that prioritized abaucin as a promising candidate, initial laboratory validation confirmed its potent antibacterial activity against . In vitro assays demonstrated that abaucin exhibits minimum inhibitory concentrations (MICs) ranging from 2 to 64 μg/mL across 42 strains, including multidrug-resistant clinical isolates, with an MIC of approximately 2 μg/mL against the reference strain ATCC 17978. These results highlight abaucin's efficacy in inhibiting bacterial growth at low micromolar concentrations, establishing its potential as a targeted therapeutic. Further characterization revealed abaucin as a narrow-spectrum agent, selectively active against Gram-negative A. baumannii with no significant inhibitory effects on such as Staphylococcus aureus or human cell lines, indicating low cytotoxicity to mammalian hosts. This selectivity was evidenced by the absence of growth inhibition in assays against diverse and human commensal bacteria like . In vivo validation was conducted using a mouse wound infection model, where abaucin administered topically as a 4% (wt/vol) cream in Glaxal Base Moisturizing Cream—applied at multiple time points (2, 3, 4, 6, 10, 21, and 24 hours post-infection)—significantly reduced bacterial load from approximately 6.9 × 10⁸ CFU/g in vehicle-treated controls to 4.0 × 10⁷ CFU/g at 25 hours post-infection. The treatment also markedly suppressed tissue compared to untreated wounds, demonstrating effective control of A. baumannii-induced without in this model. These findings were detailed in the seminal 2023 publication in Nature Chemical Biology, marking the initial peer-reviewed report on abaucin's validation.

Chemical Properties

Molecular Structure

Abaucin has the molecular formula C21_{21}H21_{21}F3_3N2_2O2_2. Its is 390.41 g·mol−1^{-1}. Abaucin is a spirocyclic compound featuring a core attached to a spiro[1H-3,1-benzoxazine-4,4'-piperidine]-2-one scaffold, with a trifluoromethyl group on the para position of the phenyl ring in the ethyl side chain. The canonical SMILES notation for abaucin is C1CN(CCC12C3=CC=CC=C3NC(=O)O2)CCC4=CC=C(C=C4)C(F)(F)F. Prior to its repurposing as an , abaucin was identified as RS-102895, a selective of the .

Synthesis and Preparation

Abaucin, also known as RS102895, originates from synthetic chemical libraries developed as of the C-C type 2 (), initially screened for applications. These libraries included off-patent drugs and proprietary synthetic compounds, such as those from Institute's collection, where abaucin was identified through machine learning-guided screening for antibacterial activity against . No dedicated patents for abaucin as an antibiotic have been filed, as its production leverages pre-existing methods from its CCR2 antagonist origins. The compound's preparation follows established synthetic routes for spiro[4H-3,1-benzoxazine] derivatives, without development of a novel pathway tailored to its role. The core spirocyclic structure is assembled by ortho-lithiation of tert-butoxycarbonyl-protected using tert-butyllithium in at -78°C, followed by addition to N-tert-butoxycarbonyl-4-piperidone, yielding the spirocyclic intermediate via spontaneous cyclization (approximately 60% yield after ). Deprotection with in , then alkylation of the nitrogen with 2-[4-(trifluoromethyl)phenyl]ethyl in the presence of Hunig's base in refluxing , affords the final product, purified by column or to >98% purity. This method is scalable and has been used commercially for research-grade supplies. For experimental use, abaucin is typically solubilized in (DMSO) at concentrations up to 1.65% (v/v) to achieve stock solutions of 50 mM or higher, given its solubility exceeding 50 mg/mL in DMSO. These stocks are then diluted into aqueous media, such as Luria-Bertani (LB) broth or (), for assays at working concentrations ranging from 1 to 50 μM. For topical applications in preclinical models, such as wound infections, abaucin is formulated at 4% (w/v) in Glaxal Base moisturizing cream containing 1.65% DMSO to ensure even distribution and stability. Abaucin exhibits good solubility in organic solvents like DMSO and dichloromethane, with limited aqueous solubility necessitating vehicle use. It remains stable under standard laboratory conditions, including incubation in LB medium at 37°C for up to 16 hours without significant degradation during growth inhibition assays.

Mechanism of Action

Target in Acinetobacter baumannii

Abaucin's primary molecular target in Acinetobacter baumannii is the LolE protein, an essential inner membrane component of the Lol lipoprotein transport system. This system is responsible for exporting lipoproteins from the inner membrane to the outer membrane, a process critical for bacterial envelope biogenesis and integrity. In A. baumannii, the Lol complex features a symmetric structure consisting of two LolD ATPases and two LolE proteins, lacking the LolC subunit found in some other Gram-negative bacteria. LolE specifically facilitates the recognition and accommodation of lipoprotein substrates during transport. Abaucin binds to and inhibits LolE function, thereby disrupting the accommodation and export of s to the outer membrane. This inhibition prevents proper lipoprotein localization, resulting in their toxic accumulation in the inner membrane. Structural predictions indicate that abaucin interacts with key residues on LolE, such as alanine 362 (A362), which is positioned near the acyl chain-binding site, thereby interfering with substrate binding and transport dynamics. Experimental evidence supports this mechanism, including whole-genome sequencing that identified resistance-conferring in lolE, such as A362T and Y394F, which reduce abaucin sensitivity by 4- to 16-fold while maintaining bacterial viability. Additionally, interference (i)-mediated knockdown of lolE lowers the (MIC) of abaucin by 4- to 8-fold, further confirming LolE as the direct target. The low frequency of resistance emergence (approximately 10⁻⁸ to 10⁻⁷) underscores the robustness of this interaction. Abaucin's selectivity for A. baumannii arises from divergence in the LolE protein sequence and structure compared to other , minimizing off-target effects. Notably, eukaryotic cells lack an equivalent LolE or analogous transport system, contributing to abaucin's narrow-spectrum activity and low to human cells.

Effects on Bacterial Physiology

Abaucin's inhibition of trafficking in leads to the mislocalization of outer membrane proteins, which in turn compromises the integrity of the cell envelope. This disruption arises from the compound's specific interference with the Lol system, responsible for transporting lipoproteins to the outer membrane. As a result, essential proteins fail to reach their proper locations, weakening the bacterial envelope's structural stability without causing direct damage to the phospholipid bilayer. Studies have shown no evidence of membrane disruption through nonspecific phospholipid bilayer damage, confirming abaucin's activity as highly target-specific rather than broadly lytic. Secondary physiological effects include impaired biogenesis of the cell envelope, which manifests as growth arrest in the bacteria without immediate cell lysis. This selective mechanism preserves host cell integrity while halting bacterial proliferation. Time-course analyses reveal that these effects begin to manifest within hours of exposure to abaucin, with notable changes observed between 4.5 and 6 hours post-treatment. During this period, immature lipoproteins accumulate due to the trafficking blockade, further exacerbating envelope defects and contributing to the overall arrest of bacterial growth. RNA sequencing data from these experiments highlight downregulation of genes involved in electron and ion transport, underscoring the broader physiological stress induced by the compound.

Antimicrobial Activity

Efficacy Against Resistant Strains

Abaucin demonstrates potent activity against , a WHO-designated critical priority , including multidrug-resistant (MDR) and carbapenem-resistant clinical isolates. testing revealed minimum inhibitory concentrations (MICs) in the range of 1–2 μg/mL across carbapenem-resistant strains, comparable to or better than many existing antibiotics like . This efficacy was consistent against 41 diverse clinical isolates harboring various intrinsic and acquired resistance mechanisms, such as β-lactamase production (e.g., OXA-23 carbapenemase), overexpression (e.g., ADE-type), and others, without loss of potency. Time-kill assays further confirmed abaucin's bactericidal effects, showing rapid reduction in viable cell counts at concentrations of 4× MIC in nutrient-replete media, achieving a 3-log decrease in colony-forming units within 4–6 hours. These results indicate strong standalone killing capability against MDR A. baumannii. Its narrow-spectrum profile contributes to this targeted action, minimizing broader ecological disruption. Abaucin's low propensity for resistance development enhances its value against MDR strains, with spontaneous resistance arising at frequencies of 10⁻⁸ to 10⁻⁷. This rarity stems from the requirement for multi-step in the target LolE protein, such as A362T or Y394F, which confer only modest 4–16-fold MIC increases individually; higher-level resistance demands additional genetic changes, complicating evolution in clinical settings.

Spectrum and Selectivity

Abaucin demonstrates a narrow antimicrobial spectrum, showing potent activity against Acinetobacter baumannii while being inactive against Gram-positive bacteria such as Staphylococcus aureus (MIC >128 μg/mL) and most other Gram-negative species, including Escherichia coli and Pseudomonas aeruginosa (MIC >128 μg/mL). This selective profile positions abaucin as a targeted therapeutic option for A. baumannii infections, minimizing off-target effects on broader bacterial populations. The compound's selectivity arises from its , which disrupts the LolE protein essential for trafficking in the outer membrane of A. baumannii; however, the basis for its species-specific activity against A. baumannii, despite the conservation of LolE in other , remains unclear. This specificity is further evidenced by resistance mutations in A. baumannii LolE (e.g., A362T, Y394F), which do not confer cross-resistance in unrelated species. Abaucin exhibits minimal cytotoxicity toward human cells, supporting a favorable safety margin for potential clinical use. Additionally, its narrow activity spares most beneficial gut and skin microbiota, such as Bifidobacterium species (no inhibition at up to 20× the MIC against A. baumannii), which could help preserve the microbiome and reduce dysbiosis risks associated with broad-spectrum antibiotics.

Therapeutic Potential

Preclinical Evaluation

Preclinical evaluation of abaucin has focused on studies in models to assess its efficacy against infections. In a model using neutropenic mice challenged with A. baumannii ATCC 17978, topical application of abaucin significantly reduced bacterial burden and mitigated inflammation compared to vehicle-treated controls. Abaucin exhibits a favorable toxicity profile aligned with its narrow-spectrum activity, sparing beneficial host microbiome components, as observed in short-term exposure studies. As of November 2025, abaucin remains in the preclinical development stage, with no human clinical trials initiated.

Challenges and Future Prospects

One primary challenge in advancing abaucin as a therapeutic agent is its narrow-spectrum activity, which is highly selective for Acinetobacter baumannii but limits its applicability to infections caused specifically by this pathogen, such as wound infections, pneumonia, and bacteremia, rather than broader bacterial threats. This selectivity, while beneficial for preserving the human microbiome by sparing commensal bacteria like Bifidobacterium species, may necessitate combination therapies or diagnostic tools to confirm A. baumannii involvement before use, complicating clinical deployment in polymicrobial or undiagnosed infections. Additionally, the potential for resistance development through mutations in the target LolE protein, such as A362T or Y394F substitutions observed in laboratory-evolved strains, poses a risk in clinical settings, though these mutants showed no cross-resistance to existing antibiotics. As of November 2025, abaucin remains in the preclinical , with demonstrated in models of A. baumannii infections but no progression to human trials reported. Opportunities for improvement include leveraging to design optimized analogs that could expand its spectrum while maintaining selectivity, building on the models that initially identified abaucin from a of approximately 7,500 compounds. Such AI-driven iterations could enhance potency against multidrug-resistant strains and address limitations, accelerating the path to (IND) filing through academic-industry partnerships. Abaucin's discovery exemplifies the role of AI in combating the global antibiotic resistance crisis, particularly for A. baumannii, a critical-priority pathogen in the World Health Organization's list and a key member of the ESKAPE group of multidrug-resistant bacteria. By targeting a novel mechanism in lipoprotein transport, it serves as a model for AI-guided development against other ESKAPE pathogens like Pseudomonas aeruginosa and Enterococcus faecium, potentially revitalizing the stagnant antibiotic pipeline amid rising resistance rates. Future directions emphasize strategic advancements, including combination regimens with existing agents like to mitigate resistance emergence, ongoing surveillance of A. baumannii isolates for LolE variants, and collaborative efforts to initiate phase I safety trials. These steps could position abaucin as a , contributing to sustainable solutions for nosocomial infections if scalability and regulatory hurdles are overcome.
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