High‐yield, plant‐based production of an antimicrobial peptide with potent activity in a mouse model

Author:

Chaudhary Shahid1ORCID,Ali Zahir1,Pantoja‐Angles Aarón1,Abdelrahman Sherin234ORCID,Juárez Cynthia Olivia Baldelamar234,Rao Gundra Sivakrishna1,Hong Pei‐Ying5,Hauser Charlotte234,Mahfouz Magdy1ORCID

Affiliation:

1. Laboratory for Genome Engineering and Synthetic Biology, Division of Biological Sciences King Abdullah University of Science and Technology (KAUST) Thuwal Jeddah Saudi Arabia

2. Laboratory for Nanomedicine, Division of Biological and Environmental Science and Engineering King Abdullah University of Science and Technology (KAUST) Thuwal Jeddah Saudi Arabia

3. Computational Bioscience Research Center King Abdullah University of Science and Technology (KAUST) Thuwal Jeddah Saudi Arabia

4. Red Sea Research Center King Abdullah University of Science and Technology (KAUST) Thuwal Jeddah Saudi Arabia

5. Water Desalination and Reuse Center, Division of Biological Sciences and Engineering King Abdullah University of Science and Technology (KAUST) Thuwal Jeddah Saudi Arabia

Abstract

SummaryPlants offer a promising chassis for the large‐scale, cost‐effective production of diverse therapeutics, including antimicrobial peptides (AMPs). However, key advances will reduce production costs, including simplifying the downstream processing and purification steps. Here, using Nicotiana benthamiana plants, we present an improved modular design that enables AMPs to be secreted via the endomembrane system and sequestered in an extracellular compartment, the apoplast. Additionally, we translationally fused an AMP to a mutated small ubiquitin‐like modifier sequence, thereby enhancing peptide yield and solubilizing the peptide with minimal aggregation and reduced occurrence of necrotic lesions in the plant. This strategy resulted in substantial peptide accumulation, reaching around 2.9 mg AMP per 20 g fresh weight of leaf tissue. Furthermore, the purified AMP demonstrated low collateral toxicity in primary human skin cells, killed pathogenic bacteria by permeabilizing the membrane and exhibited anti‐infective efficacy in a preclinical mouse (Mus musculus) model system, reducing bacterial loads by up to three orders of magnitude. A base‐case techno‐economic analysis demonstrated the economic advantages and scalability of our plant‐based platform. We envision that our work can establish plants as efficient bioreactors for producing preclinical‐grade AMPs at a commercial scale, with the potential for clinical applications.

Publisher

Wiley

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