Antimicrobial resistance (AMR) is rapidly outpacing antibiotic development, posing a critical global health threat. Many resistance mechanisms are mediated by specific bacterial proteins, suggesting that designing binders to inhibit these targets, alongside discovering novel antimicrobial peptides (AMPs) offers a promising therapeutic strategy. Here, we introduce AMP-BindGen, a framework that explores the ability of modern protein design methods to jointly address targeted binding and antimicrobial activity. Building on Boltzgen, we guide sequence generation using an external AMP predictor, Macrel, effectively coupling structural/biophysical design with functional antimicrobial constraints. Our approach first generates diverse peptide candidates using a flexible generative prior trained on AMP-like sequences. We then incorporate activity-aware guidance through Macrel-based scoring, applying rejection sampling, soft reweighting, and diversity-preserving selection to approximate the conditional distribution of peptides with high antimicrobial potential. This allows us to explicitly bias generation toward functional AMPs while retaining sequence diversity. Importantly, we extend this paradigm beyond unconstrained AMP generation by evaluating whether binder design frameworks can be repurposed to produce AMPs that also target key AMR-related proteins, bridging two traditionally separate design objectives: binder design and antimicrobial function. In silico results show that AMP-BindGen significantly enriches sequences with high predicted antimicrobial activity compared to unguided generation, while maintaining broad physicochemical diversity. Our findings suggest that integrating binder design principles with AMP activity guidance provides a powerful and practical route for generating multifunctional peptide candidates, opening new directions for combating antimicrobial resistance. Adding Guidance doubled the generated binders' AMP-likeliness while maintaining binding metrics.

Co-authors: Attila Gürsoy, Ozlem Keskin, Ani Akpinar, Fusun Can, Önder Ergönül, Erkmen Erken, Eylül Sevinç Sevinç