Rational Design of a Novel α-Helical Antimicrobial Peptide Targeting Salmonella typhi

The global rise of multidrug-resistant and extensively drug-resistant (XDR) Salmonella enterica serovar Typhi poses a large threat to treatment of typhoid fever. Traditional antibiotics are increasingly threatened, which explains the dire need for novel therapeutics. Antimicrobial peptides (AMPs), particularly α-helical variants, are increasingly promising alternatives because of their membrane-disruptive mechanisms and reduced resistance likelihood. In this study, we utilized a rational in silico design workflow to generate and optimize an AMP candidate that targets S. Typhi. Using GRAMPA as the source, combined with CAMPr3/4 for activity prediction, DBAASP and APD3 for physicochemical profiling, ToxinPred for toxicity screening, and AlphaFold for structural modeling, 30 peptide variants were computationally evaluated. Through detailed screening, we identified Sur-Helix1 (AKKLKAVLRIKRLLRK), a 16-residue α-helical peptide with a net charge of +5, stable helical structure, strong antimicrobial probability, and low hemolytic potential. These findings demonstrate the potential of computationally guided AMP design to create optimized, non-toxic candidates against S. Typhi . This study establishes a framework for rational peptide engineering and shows Sur-Helix1 as a promising candidate for future experimental validation and development.