Formulation and Biological Evaluation of Mesoporous Silica Nanoparticles Loaded with Combinations of Sortase A Inhibitors and Antimicrobial Peptides

Sitah Alharthi; Zyta M Ziora; Taskeen Janjua; Amirali Popat; Peter M Moyle

doi:10.3390/pharmaceutics14050986

Formulation and Biological Evaluation of Mesoporous Silica Nanoparticles Loaded with Combinations of Sortase A Inhibitors and Antimicrobial Peptides

Pharmaceutics. 2022 May 4;14(5):986. doi: 10.3390/pharmaceutics14050986.

Authors

Sitah Alharthi^{1

2}, Zyta M Ziora³, Taskeen Janjua¹, Amirali Popat^{1

4}, Peter M Moyle¹

Affiliations

¹ School of Pharmacy, The University of Queensland, Pharmacy Australia Centre of Excellence, 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, Saint. Lucia, QLD 4072, Australia.
⁴ Mater Research Institute, The University of Queensland, Translational Research Institute, 37 Kent St., Woolloongabba, QLD 4102, Australia.

Abstract

This study aimed to develop synergistic therapies to treat superbug infections through the encapsulation of sortase A inhibitors (SrtAIs; trans-chalcone (TC), curcumin (CUR), quercetin (QC), or berberine chloride (BR)) into MCM-41 mesoporous silica nanoparticles (MSNs) or a phosphonate-modified analogue (MCM-41-PO₃^-) to overcome their poor aqueous solubility. A resazurin-modified minimum inhibitory concentration (MIC) and checkerboard assays, to measure SrtAI synergy in combination with leading antimicrobial peptides (AMPs; pexiganan (PEX), indolicidin (INDO), and [I5, R8] mastoparan (MASTO)), were determined against methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. The results demonstrated that the MCM-41 and MCM-41-PO₃^- formulations significantly improved the aqueous solubility of each SrtAI. The MICs for SrtAI/MCM-41-PO₃^- formulations were lower compared to the SrtAI/MCM-41 formulations against tested bacterial strains, except for the cases of BR/MCM-41 and QC/MCM-41 against P. aeruginosa. Furthermore, the following combinations demonstrated synergy: PEX with TC/MCM-41 (against all strains) or TC/MCM-41-PO₃^- (against all strains except P. aeruginosa); PEX with BR/MCM-41 or BR/MCM-41-PO₃^- (against MSSA and MRSA); INDO with QC/MCM-41 or QC/MCM-41-PO₃^- (against MRSA); and MASTO with CUR/MCM-41 (against E. coli). These combinations also reduced each components' toxicity against human embryonic kidney cells. In conclusion, MCM-41 MSNs provide a platform to enhance SrtAI solubility and demonstrated antimicrobial synergy with AMPs and reduced toxicity, providing novel superbug treatment opportunities.

Keywords: antimicrobial peptides; antimicrobial resistance; mesoporous silica nanoparticles; sortase A inhibitors; synergy.

Abstract

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