In vitro and in silico effect of meldrum's acid-derived compounds on Staphylococcus aureus strains as NorA efflux pump inhibitors

• Published in: Biophysical chemistry 2025-01, Vol.316, p.107344, Article 107344
• Main Authors: Araújo, Isaac Moura, Pereira, Raimundo Luiz Silva, de Araújo, Ana Carolina Justino, Gonçalves, Sheila Alves, Tintino, Saulo Relison, de Morais Oliveira-Tintino, Cícera Datiane, de Menezes, Irwin Rose Alencar, Salamoni, Renata, Begnini, Iêda Maria, Rebelo, Ricardo Andrade, da Silva, Luiz Everson, Domiciano, Carolina Bandeira, Coutinho, Henrique Douglas Melo
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Dioxanes - chemistry; Dioxanes - pharmacology; Efflux pump; Meldrum acid derivates; Microbial Sensitivity Tests; Molecular Docking Simulation; Multidrug Resistance-Associated Proteins - antagonists & inhibitors; Multidrug Resistance-Associated Proteins - metabolism; NorA; Staphylococcus aureus - drug effects; Staphylococcus aureus - metabolism
• ISSN: 0301-4622; 1873-4200; 1873-4200
• DOI: 10.1016/j.bpc.2024.107344

The misuse of antibiotics has led to an alarming increase in bacterial strains resistant to these drugs. Efflux pumps, which expel antibiotics from bacterial cells, have emerged as one of the key mechanisms of bacterial resistance. In the quest to combat and mitigate bacterial resistance, researchers have turned their attention to efflux pump inhibitors as a potential solution. Meldrum's acid, a synthetic molecule widely utilized in the synthesis of bioactive compounds, has garnered significant interest in this regard. Hence, this study aims to investigate the antibacterial activity and evaluate the efficacy of three derivatives of meldrum's acid in inhibiting efflux mechanisms, employing both in silico and in vitro approaches. The antibacterial activity of the derivatives was assessed through rigorous broth microdilution testing. While the derivatives themselves did not exhibit direct antibacterial activity, they demonstrated remarkable potential in potentiating the effects of antibiotics. Additionally, fluorescence emission assays using ethidium bromide (EtBr) revealed fluorescence levels comparable to the positive control, indicating a possible blockade of efflux pumps. Molecular docking studies conducted in silico further supported these findings by revealing binding interactions similar to norfloxacin and CCCP, known efflux pump inhibitors. These results underscore the potential of meldrum's acid derivatives as effective inhibitors of efflux pumps. By inhibiting these mechanisms, the derivatives hold promise in enhancing the effectiveness of antibiotics and combatting bacterial resistance. This study contributes valuable insights into the development of novel strategies to address the pressing issue of bacterial resistance and paves the way for further research and exploration in this field. [Display omitted] •The meldrum's acid derivatives have a lot biological activities described on literature.•The meldrum's acid derivatives increased the antibiotics and ethidium bromide effects.•They possibly blocked the NorA efflux pump by the increased the intensity of fluorescence emission of ethidium bromide.•Docking simulations indicate that the synthesized compounds have the potential to interact with the efflux systems of NorA.