# Machine Learning-Identified Potent Antimicrobial Peptides Against Multidrug-Resistant Bacteria and Skin Infections

## TL;DR

Machine learning helps discover new antimicrobial peptides that effectively fight drug-resistant bacteria and skin infections.

## Contribution

ML model identifies potent AMPs against MDR bacteria and skin infections, validated experimentally.

## Key findings

- GDST-038 and GDST-045 peptides show strong activity against Acinetobacter baumannii and Staphylococcus aureus.
- Retro-inverso variants of GDST peptides demonstrate enhanced biofilm killing of A. baumannii.
- GDST peptides achieve significant reduction in S. aureus biofilm and work in a 3D skin infection model without resistance development.

## Abstract

Background: The escalating global crisis of antibiotic resistance necessitates the discovery of novel antimicrobial agents. Antimicrobial peptides (AMPs) represent a promising alternative to combat multidrug-resistant (MDR) pathogens. Because traditional AMP discovery is labour-intensive and costly, machine learning (ML) is applied to identify AMPs effective against MDR bacteria and skin infections. Methods: The ML-based CalcAMP model predicts the antimicrobial activity of 16,384 unique 14-amino-acid peptide sequences, resulting in a novel Guided Designed Smart antimicrobial Therapeutic (GDST) peptide catalogue. Parent sequences and retro-inverso (RI) variants of two prime GDST peptides undergo extensive testing against MDR bacteria and in skin infection models. Results: GDST-038 and GDST-045, along with their RI variants, show potent antimicrobial activity against Acinetobacter baumannii and Staphylococcus aureus, rapidly depolarizing the cytoplasmic membrane, exhibiting broad-spectrum bactericidal effects against ESKAPE pathogens, and causing minimal haemolysis. RI variants display superior A. baumannii biofilm killing compared to parent sequences, while all GDST peptides achieve >3-log reductions in S. aureus biofilm CFU within 24 h. Potent efficacy is observed in a 3D human skin epidermal infection model, with elimination of S. aureus at ≥15 μM. No resistance develops after 22 passages. Conclusions: ML-driven screening enables rapid identification of two novel candidate AMPs, highlighting the therapeutic potential of GDST peptides for MDR bacterial infections.