AMPBench-MT: A Homology-Controlled Benchmark for Antimicrobial Peptide Potency, Spectrum, and Safety Prediction

Antimicrobial peptides (AMPs) often act against multiple pathogen classes, making multi-label activity prediction a more realistic screening target than binary antimicrobial classification. The ESCAPE benchmark formalizes this setting, but leading approaches typically rely on multimodal, structure-conditioned deep models that are costly to train and tune. We show that a simple, sequence-only pipeline can match and surpass these methods by combining 330 interpretable sequence descriptors with TabPFN, a tabular foundation model that performs in-context prediction in a single forward pass without gradient-based training or hyperparameter search. On ESCAPE (82,359 peptides; five labels), a label-powerset TabPFN model achieves mAP-5 = 77.8%, improving on the previously best reported 72.1%. A probabilistic classifier chain is the first method to match or exceed the best published average precision on each of the five labels simultaneously. The gains persist under the prior state-of-the-art single-fold training protocol, indicating they are not a training-set-size artefact, and are largest for remote homologues (+11.2 points below 30% sequence identity). Ablations further show that predicted structure is unnecessary at inference and that performance is not driven by any single descriptor family: ten global physicochemical scalars recover 91% of full-feature performance. Finally, explicitly modelling label dependence yields targeted benefits for scarce activities and supports ranking which activity to assay next from partial positive evidence.

Antimicrobial resistance causes to over a million deaths annually. Antimicrobial peptides (AMPs) are a promising solution, but generative AMP models are not yet ready to design peptides with non-natural amino acids and/or chemical modifications, which are essential for real-world peptide drugs. We present AMPGAN v3, a multi-objective conditional GAN that expands the generative vocabulary to D-amino acids and N/C-terminus modifications such as amidation. By separating adversarial and activity-aware supervision across two specialized discriminators, AMPGAN v3 substantially improves training stability and outperforms prior generative AMP models on external classifiers. We validated five candidates spanning three structural classes in vitro; two showed activity against Gram-positive strains, with the best candidate reaching MIC 8 μg/mL against B. subtilis. To support downstream curation, we further present PepCraft, a multi-agent framework for end-to-end AMP discovery in which a Planning Agent orchestrates specialized executors for generation, filtering, and verification. Its prioritization recommendations align with our in vitro outcomes. Together, these contributions let us examine, on a small but real scale, how generative and agentic AI compose in therapeutic peptide discovery. Code: https://github.com/marszzibros/AMPGANv3

Deep learning-based antimicrobial peptide (AMP) discovery faces critical challenges such as limited controllability, lack of representations that efficiently model antimicrobial properties, and low experimental hit rates. To address these challenges, we introduce OmegAMP, a framework designed for reliable AMP generation with increased controllability. Its diffusion-based generative model leverages a novel conditioning mechanism to achieve fine-grained control over desired physicochemical properties and to direct generation towards specific activity profiles, including species-specific effectiveness. This is further enhanced by a biologically informed encoding space that significantly improves overall generative performance. Complementing these generative capabilities, OmegAMP leverages a novel synthetic data augmentation strategy to train classifiers for AMP filtering, drastically reducing false positive rates and thereby increasing the likelihood of experimental success. Our in silico experiments demonstrate that OmegAMP delivers state-of-the-art performance across key stages of the AMP discovery pipeline, enabling us to achieve an unprecedented success rate in wet lab experiments. We tested 25 candidate peptides, 24 of them (96%) demonstrated antimicrobial activity, proving effective even against multi-drug resistant strains. Our findings underscore OmegAMP's potential to significantly advance computational frameworks in the fight against antimicrobial resistance.