From Mitochondrial Targeting to Microbial Killing: Twinkle-Derived Peptides as an Emerging Class of Potent AMPs
4 affiliations
- 1Institute of Biosciences and BioResources (IBBR)─National Research Council (CNR) , ,
- 2University of Naples Federico II , , ,
- 3University of Split , , ,
- 4University of Split School of Medicine , , ,
Abstract
Mitochondrial targeting sequences are short N-terminal peptides that direct proteins to mitochondria. Notably, their amphipathic α-helical architecture closely resembles that of many potent antimicrobial peptides (AMPs). This structural convergence reflects the endosymbiotic origin of mitochondria and suggests that contemporary mitochondrial targeting sequences may retain latent antimicrobial properties. Here, this evolutionary link was exploited to investigate the mitochondrial-targeting sequences of a Twinkle helicase as a scaffold for the rational design of a new class of antimicrobials. Using an in silico strategy, two peptides, TAMP1 (Twinkle AntiMicrobial Peptide1) and its optimized derivative, TAMP2 (Twinkle AntiMicrobial Peptide2), were designed starting from the mitochondrial targeting sequences of the Twinkle helicase from the Antarctic fish Notothenia coriiceps. Both 18-residue peptides were structurally and functionally characterized as proof of concept for mitochondrial targeting sequence-derived antimicrobials. They adopted stable amphipathic α-helical conformations and exhibited antimicrobial activity against both Gram-positive and Gram-negative bacteria. Notably, TAMP2 demonstrated enhanced efficacy, effectively targeting an extended panel of bacteria, including spoilage, foodborne, and multidrug-resistant pathogens, with MBC values in the range of 0.5–32 μM. Microscale thermophoresis and molecular dynamics simulations further supported these observations, indicating strong interactions with bacterial membrane mimetics and providing mechanistic insight into peptide activity. These findings establish Twinkle-derived mitochondrial targeting sequence peptides as a promising, scalable platform for developing a novel class of antimicrobial agents inspired by mitochondrial evolution.
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BibTeX
@article{porritiello2026from,
title = {{From Mitochondrial Targeting to Microbial Killing: Twinkle-Derived Peptides as an Emerging Class of Potent AMPs}},
author = {Alessandra Porritiello and Emanuela Galatola and Bruna Agrillo and Monica Ambrosio and Marco Balestrieri and Marta Gogliettino and Ennio Cocca and Adele Adamo and Natascia Marciano and Rosa Luisa Ambrosio and Tomislav Rončević and Iva Stojan and Larisa Zoranić and Anamarija Budimir and Sandra Marijan and Aniello Anastasio and Gianna Palmieri},
journal = {ACS Omega},
year = {2026},
month = nov,
doi = {10.1021/acsomega.6c08726},
url = {https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c08726/5462669/From-Mitochondrial-Targeting-to-Microbial-Killing},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - From Mitochondrial Targeting to Microbial Killing: Twinkle-Derived Peptides as an Emerging Class of Potent AMPs
AU - Alessandra Porritiello
AU - Emanuela Galatola
AU - Bruna Agrillo
AU - Monica Ambrosio
AU - Marco Balestrieri
AU - Marta Gogliettino
AU - Ennio Cocca
AU - Adele Adamo
AU - Natascia Marciano
AU - Rosa Luisa Ambrosio
AU - Tomislav Rončević
AU - Iva Stojan
AU - Larisa Zoranić
AU - Anamarija Budimir
AU - Sandra Marijan
AU - Aniello Anastasio
AU - Gianna Palmieri
PY - 2026
DA - 2026/11/03
JO - ACS Omega
DO - 10.1021/acsomega.6c08726
UR - https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c08726/5462669/From-Mitochondrial-Targeting-to-Microbial-Killing
AB - Mitochondrial targeting sequences are short N-terminal peptides that direct proteins to mitochondria. Notably, their amphipathic α-helical architecture closely resembles that of many potent antimicrobial peptides (AMPs). This structural convergence reflects the endosymbiotic origin of mitochondria and suggests that contemporary mitochondrial targeting sequences may retain latent antimicrobial properties. Here, this evolutionary link was exploited to investigate the mitochondrial-targeting sequences of a Twinkle helicase as a scaffold for the rational design of a new class of antimicrobials. Using an in silico strategy, two peptides, TAMP1 (Twinkle AntiMicrobial Peptide1) and its optimized derivative, TAMP2 (Twinkle AntiMicrobial Peptide2), were designed starting from the mitochondrial targeting sequences of the Twinkle helicase from the Antarctic fish Notothenia coriiceps. Both 18-residue peptides were structurally and functionally characterized as proof of concept for mitochondrial targeting sequence-derived antimicrobials. They adopted stable amphipathic α-helical conformations and exhibited antimicrobial activity against both Gram-positive and Gram-negative bacteria. Notably, TAMP2 demonstrated enhanced efficacy, effectively targeting an extended panel of bacteria, including spoilage, foodborne, and multidrug-resistant pathogens, with MBC values in the range of 0.5–32 μM. Microscale thermophoresis and molecular dynamics simulations further supported these observations, indicating strong interactions with bacterial membrane mimetics and providing mechanistic insight into peptide activity. These findings establish Twinkle-derived mitochondrial targeting sequence peptides as a promising, scalable platform for developing a novel class of antimicrobial agents inspired by mitochondrial evolution.
SN - 2470-1343
ER -