Caesalpinia ferrea C. Mart., popularly known as “Jucá” or “Pau-ferro”, belongs to the Fabaceae family, and is classified as a native and endemic species in Brazil. Numerous studies that portray its ethnobotany, chemical composition, and biological activities exist in the literature. The present study aimed to systematically review publications addressing the botanical aspects, uses in popular medicine, phytochemical composition, and bioactivities of C. ferrea. The searches focused on publications from 2015 to March 2020 using the Scopus, Periódicos Capes, PubMed, Google Scholar, and ScienceDirect databases. The leaves, fruits, seeds, and bark from C. ferrea are used in popular medicine to treat disorders affecting several systems, including the circulatory, immune, cardiovascular, digestive, respiratory, genitourinary, musculoskeletal, and conjunctive systems. The most commonly found chemical classes in phytochemical studies are flavonoids, polyphenols, terpenoids, tannins, saponins, steroids, and other phenolic compounds. The biological properties of the extracts and isolated compounds of C. ferrea most cited in the literature were antibacterial, antifungal, antioxidant, antiproliferative, anti-inflammatory, and healing potential. However, further studies are still needed to clarify a link between its traditional uses, the active compounds, and the reported pharmacological activities, as well as detailed research to determine the toxicological profile of C. ferrea.

The Gram-positive bacterium Staphylococcus aureus is responsible for a number of infections and has been described to exhibit resistance to antibacterial drugs through different resistance mechanisms. Among these, active efflux has been shown to be one of the main mechanisms of bacterial resistance associated with S. aureus. In this sense, the aim of the present study was to evaluate the ability of ellagic acid and gallic acid to reverse resistance by inhibiting the efflux pumps present in S. aureus strains IS-58 and K2068, which express the TetK and MepA flux pumps, respectively. In addition, the toxicity of both compounds was verified in Drosophila melanogaster. Broth microdilution assays were performed to obtain the minimum inhibitory concentration (MIC) values of ellagic acid and gallic acid, whereas efflux pump inhibition was tested using a subinhibitory concentration of standard efflux pump inhibitors, gallic acid and ellagic acid (MIC/8), where the ability of these compounds to decrease the MIC of ethidium bromide (EtBr) and antibiotics was verified. Toxicity was evaluated by mortality and negative geotaxis assays in D. melanogaster. Ellagic acid and gallic acid showed no direct antibacterial activity on S. aureus strains carrying the efflux pumps TetK and MepA. However, when we looked at the results for the TetK pump, we saw that when the two acids were associated with the antibiotic tetracycline, a potentiation of the antibacterial effect occurred; this behavior was also observed for the antibiotic ciprofloxacin in the MepA strain. For the efflux pump inhibition results, only the compound gallic acid showed potentiating effect on antibacterial activity when associated with the substrate EtBr for the IS-58 strain carrying the TetK efflux pump. Ellagic acid and gallic acid showed no toxicity on the model arthropod D. melanogaster. These results indicate the possible use of gallic acid as an adjuvant in antibiotic therapy against multidrug-resistant bacteria.

Background/Objectives: The increasing prevalence of multidrug-resistant Staphylococcus aureus represents a major clinical challenge, primarily driven by the acquisition of multiple resistance mechanisms. Among these, efflux pumps such as NorA play a pivotal role in quinolone resistance by promoting active drug extrusion and reducing intracellular antibiotic levels. This study evaluated the synthetic chalcone CMA4DMA as a potential NorA efflux pump inhibitor and modulator of bacterial resistance. Methods: Antimicrobial susceptibility assays were conducted against S. aureus SA1199 (wild-type) and SA1199B (NorA-overexpressing) strains. The minimum inhibitory concentration (MIC) of CMA4DMA and its modulatory effects on norfloxacin and ethidium bromide were determined. Efflux inhibition was assessed by ethidium bromide accumulation and SYTOX Green assays. Molecular docking and in silico ADMET analyses were performed to predict binding affinity and pharmacokinetic parameters. Results: CMA4DMA exhibited no intrinsic antibacterial activity (MIC ≥ 1024 µg/mL) but reduced the MIC of norfloxacin from 32 to 8 µg/mL and that of ethidium bromide from 32 to 8 µg/mL in SA1199. In SA1199B, reductions from 64 to 16 µg/mL and from 64 to 32 µg/mL were observed, respectively. Fluorescence increased by 15% without affecting membrane integrity. Docking revealed a binding affinity of −7.504 kcal/mol, stronger than norfloxacin (−7.242 kcal/mol), involving key residues Leu218, Ile309, Arg310, and Ile313. ADMET data indicated high intestinal absorption (88.76%) and permeability (Papp = 1.38 × 10⁻⁵ cm/s). Conclusions: CMA4DMA effectively restored norfloxacin susceptibility in resistant S. aureus strains, highlighting its potential as a promising scaffold for developing novel efflux pump inhibitors and antibiotic adjuvants.

The emergence of efflux-mediated resistance in Staphylococcus aureus has limited the effectiveness of conventional antibiotics, highlighting the need for novel adjuvant compounds. This study investigated the synthetic chalcone CMA4DMA as a potential modulator of bacterial resistance associated with the NorA efflux pump. In vitro anti-microbial assays showed that CMA4DMA displayed no intrinsic antibacterial effect (MIC ≥ 1024 µg/mL) but significantly reduced the minimum inhibitory concentration of norfloxacin and ethidium bromide in both wild-type SA1199 and NorA-overexpressing SA1199B strains. Fluorescence assays demonstrated increased intracellular accumulation of ethidium bromide without affecting membrane permea-bility, supporting an efflux-inhibitory mechanism. Molecular docking analysis revealed that CMA4DMA binds to the same site as norfloxacin in the NorA protein, engaging in hydrophobic and hydrogen-bond interactions with key residues, consistent with direct inhibition. In silico ADMET predictions indicated favorable oral absorption and distri-bution, though possible rapid metabolism and risks of hepatotoxicity and cardiotoxici-ty warrant caution for further development. Overall, CMA4DMA effectively restored antibiotic susceptibility in resistant S. aureus strains and showed a consistent inhibitory effect when compared with studies involving other efflux systems, reinforcing its po-tential as a promising scaffold for the development of new bacterial resistance modu-lators.