Designing antimicrobials with programmable mechanism and safety

Abstract

Antimicrobial peptides (AMPs) are a promising solution to antimicrobial resistance, yet generative models for their design cannot control the physicochemical properties and motifs that shape activity and selectivity. Here, we present OmegAMP, a conditional diffusion framework controlling net charge, mean hydrophobicity, and sequence length, supporting de novo, analog, and motif-guided design. Across 204 wet-lab characterized peptides, de novo generation yielded antimicrobials with broad activity against multidrug-resistant Gram-negative isolates. Analog generation converted six inactive prototypes into antimicrobials, with the prototype determining each analog's membrane-disruption mode and mammalian-cell safety. Motif-guided analog generation preserved lipopolysaccharide engagement of active prototypes, and a redesigned non-antimicrobial leucine zipper acquired antimicrobial activity while retaining DNA-perturbing character in vitro. In murine skin and thigh infection models, leads reduced bacterial burden, with a motif-guided DNA-perturbing lead matching the fluoroquinolone control systemically. OmegAMP opens a programmable route to new peptide antibiotics whose mechanism and safety follow from the chosen prototype.

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Cite

BibTeX RIS

BibTeX

@misc{szymczak2026designing,
  title = {{Designing antimicrobials with programmable mechanism and safety}},
  author = {P. Szymczak and M. D. T. Torres and D. Soares and L. Hetzel and B. Puczko-Szymanski and S. Jegelka and S. Günnemann and F. J. Theis and C. de la Fuente-Nunez and E. Szczurek},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.01.747572},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.01.747572v1},
  note = {CC BY-ND},
}

RIS

TY  - UNPB
TI  - Designing antimicrobials with programmable mechanism and safety
AU  - P. Szymczak
AU  - M. D. T. Torres
AU  - D. Soares
AU  - L. Hetzel
AU  - B. Puczko-Szymanski
AU  - S. Jegelka
AU  - S. Günnemann
AU  - F. J. Theis
AU  - C. de la Fuente-Nunez
AU  - E. Szczurek
PY  - 2026
DA  - 2026/09/01
PB  - bioRxiv
DO  - 10.64898/2026.09.01.747572
UR  - https://www.biorxiv.org/content/10.64898/2026.09.01.747572v1
AB  - Antimicrobial peptides (AMPs) are a promising solution to antimicrobial resistance, yet generative models for their design cannot control the physicochemical properties and motifs that shape activity and selectivity. Here, we present OmegAMP, a conditional diffusion framework controlling net charge, mean hydrophobicity, and sequence length, supporting de novo, analog, and motif-guided design. Across 204 wet-lab characterized peptides, de novo generation yielded antimicrobials with broad activity against multidrug-resistant Gram-negative isolates. Analog generation converted six inactive prototypes into antimicrobials, with the prototype determining each analog's membrane-disruption mode and mammalian-cell safety. Motif-guided analog generation preserved lipopolysaccharide engagement of active prototypes, and a redesigned non-antimicrobial leucine zipper acquired antimicrobial activity while retaining DNA-perturbing character in vitro. In murine skin and thigh infection models, leads reduced bacterial burden, with a motif-guided DNA-perturbing lead matching the fluoroquinolone control systemically. OmegAMP opens a programmable route to new peptide antibiotics whose mechanism and safety follow from the chosen prototype.
ER  -

Abstract

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