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This study aimed to develop synergistic therapies to treat superbug infections through the encapsulation of sortase A inhibitors (SrtAIs; <i>trans</i>-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) <i>Staphylococcus aureus</i>, <i>Escherichia coli</i>, and <i>Pseudomonas aeruginosa</i>. 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 <i>P. aeruginosa</i>. Furthermore, the following combinations demonstrated synergy: PEX with TC/MCM-41 (against all strains) or TC/MCM-41-PO₃⁻ (against all strains except <i>P. aeruginosa</i>); 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 <i>E. coli</i>). 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.