Sortase A Inhibitor Protein Nanoparticle Formulations Demonstrate Antibacterial Synergy When Combined with Antimicrobial Peptides

Author:

Alharthi Sitah12ORCID,Popat Amirali1,Ziora Zyta Maria3,Moyle Peter Michael1ORCID

Affiliation:

1. School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, QLD 4102, Australia

2. Department of Pharmaceutical Science, School of Pharmacy, Shaqra University, Riyadh 11961, Saudi Arabia

3. Institute for Molecular Bioscience (IMB), The University of Queensland, St Lucia, QLD 4072, Australia

Abstract

Sortase A (SrtA) is an enzyme which attaches proteins, including virulence factors, to bacterial cell walls. It is a potential target for developing anti-virulence agents against pathogenic and antimicrobial resistant bacteria. This study aimed to engineer 𝛽-lactoglobulin protein nanoparticles (PNPs) for encapsulating safe and inexpensive natural SrtA inhibitors (SrtAIs; trans-chalcone (TC), curcumin (CUR), quercetin (QC), and berberine (BR)) to improve their poor aqueous dispersibility, to screen for synergy with antimicrobial peptides (AMPs), and to reduce the cost, dose, and toxicity of AMPs. Minimum inhibitory concentration (MIC), checkerboard synergy, and cell viability assays were performed for SrtAI PNPs against Gram-positive (methicillin-sensitive and -resistant S. aureus) and Gram-negative (E. coli, P. aeruginosa) bacteria alone and combined with leading AMPs (pexiganan, indolicidin, and a mastoparan derivative). Each SrtAI PNP inhibited Gram-positive (MIC: 62.5–125 µg/mL) and Gram-negative (MIC: 31.3–500 µg/mL) bacterial growth. TC PNPs with pexiganan demonstrated synergy against each bacteria, while BR PNPs with pexiganan or indolicidin provided synergy towards S. aureus. Each SrtAI PNP inhibited SrtA (IC50: 25.0–81.8 µg/mL), and did not affect HEK-293 cell viability at their MIC or optimal synergistic concentrations with AMPs. Overall, this study provides a safe nanoplatform for enhancing antimicrobial synergy to develop treatments for superbug infections.

Funder

School of Pharmacy at University of Queensland

Faculty of Health and Behavioural Sciences

Shaqra University

Metagenics

Publisher

MDPI AG

Subject

Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science

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