Adjuvant Effect of Meldrum’s Acid Derivatives on Antibiotic Activity Against Multidrug-Resistant Bacteria
Isaac Moura Araújo, Ewerton Yago de Sousa Rodrigues, Daniel Sampaio Alves, Clara Mariana Gonçalves Lima, Sheila Alves Gonçalves, Cícera Georgia Brito Milfont, Alisson Justino Alves da Silva, João Arthur de Oliveira Borges, Cícera Datiane de Morais Oliveira-Tintino, Samara Alves Brito, José Thyálisson da Costa Silva, Francisco Assis Bezerra da Cunha, Ricardo Andrade Rebelo, Iêda Maria Begnini, Renata Salamoni, Luiz Everson da Silva, Nathalia Monteiro Lins Freire, Renata Ferreira Santana, Thiago Mendonça de Aquino, Saulo Relison Tintino, Henrique Douglas Melo CoutinhoAntimicrobial resistance demands new strategies capable of restoring the effectiveness of conventional antibiotics. In this study, the antibacterial activity and adjuvant potential of five Meldrum’s acid derivatives (MAD1–MAD5) against multidrug-resistant strains of Staphylococcus aureus 10 and Escherichia coli 06 were evaluated. Minimum inhibitory concentrations (MICs) were determined by broth microdilution, and the combined effects with ampicillin, gentamicin, and norfloxacin were analyzed at subinhibitory concentrations. Membrane permeability was assessed by SYTOX Green fluorescence, and bacterial energy metabolism was assessed by quantifying intracellular ATP using bioluminescence. The derivatives did not show direct antibacterial activity (MIC ≥ 1024 µg/mL), but they significantly reduced the MICs of the antibiotics, especially gentamicin and norfloxacin. Increased membrane permeability and reduced ATP levels were most evident in E. coli, particularly for MAD3, MAD4, and MAD5, while S. aureus showed a limited response. In silico ADMET predictions indicated pharmacokinetic profiles consistent with bioactive compounds. Taken together, the results demonstrate that Meldrum’s acid derivatives act as species-dependent modulators of antimicrobial resistance, highlighting their potential as antibacterial adjuvants.