Meldrum's acid derivates are MepA efflux pump inhibitors: In vitro and in silico essays.

Efflux pumps are proteins capable of expelling antibiotics from bacterial cells, have emerged as a major mechanism of bacterial resistance. In the ongoing pursuit to overcome and reduce bacterial resistance, novel substances are being explored as potential efflux pump inhibitors. Meldrum's acid, a synthetic molecule widely studied for its role in synthesizing bioactive compounds, holds promise in this regard. Therefore, the objective of this study is to evaluate the antibacterial activity of three derivatives of Meldrum's acid and assess their ability to inhibit efflux mechanisms, employing both in silico and in vitro approaches. The antibacterial activity of the derivatives was assessed using a broth microdilution testing method. Surprisingly, the derivatives did not exhibit direct antibacterial activity on their own. However, they displayed a significant effect in enhancing the efficacy of antibiotics, suggesting a potential role in potentiating their effects. Furthermore, fluorescence emission assays using ethidium bromide indicated that the derivatives could potentially block efflux pumps, as they exhibited fluorescence levels comparable to the positive control. To further investigate their inhibitory capacity, molecular docking studies were conducted in silico, revealing binding interactions similar to ciprofloxacin and carbonyl cyanide 3-chlorophenylhydrazone, known efflux pump inhibitors. These findings highlight the potential of Meldrum's acid derivatives as effective inhibitors of efflux pumps. By targeting these mechanisms, the derivatives offer a promising avenue to enhance the effectiveness of antibiotics and combat bacterial resistance. This study underscores the importance of exploring novel strategies in the fight against bacterial resistance and provides valuable insights into the potential of Meldrum's acid derivatives as efflux pump inhibitors. Further research and exploration in this field are warranted to fully exploit their therapeutic potential.

Efflux Pump (QacA, QacB, and QacC) and ß-Lactamase Inhibitors? An Evaluation of 1,8-Naphthyridines against Staphylococcus aureus Strains.

The bacterial species Staphylococcus aureus presents a variety of resistance mechanisms, among which the expression of ß-lactamases and efflux pumps stand out for providing a significant degree of resistance to clinically relevant antibiotics. The 1,8-naphthyridines are nitrogen heterocycles with a broad spectrum of biological activities and, as such, are promising research targets. However, the potential roles of these compounds on bacterial resistance management remain to be better investigated. Therefore, the present study evaluated the antibacterial activity of 1,8-naphthyridine sulfonamides, addressing their ability to act as inhibitors of ß-lactamases and efflux pump (QacA/B and QacC) against the strains SA-K4414 and SA-K4100 of S. aureus. All substances were prepared at an initial concentration of 1024 µg/mL, and their minimum inhibitory concentrations (MIC) were determined by the broth microdilution method. Subsequently, their effects on ß-lactamase- and efflux pump-mediated antibiotic resistance was evaluated from the reduction of the MIC of ethidium bromide (EtBr) and ß-lactam antibiotics, respectively. The 1,8-naphthyridines did not present direct antibacterial activity against the strains SA-K4414 and SA-K4100 of S. aureus. On the other hand, when associated with antibiotics against both strains, the compounds reduced the MIC of EtBr and ß-lactam antibiotics, suggesting that they may act by inhibiting ß-lactamases and efflux pumps such as QacC and QacA/B. However, further research is required to elucidate the molecular mechanisms underlying these observed effects.

Chemical Profile and Biological Activities of Essential Oil from Piper arboreum for Development and Improvement of Mouthwash.

Studies show that more consumers are using natural health products in the modern world. We have noticed a growing demand in markets and the professional community for mouthwashes that contain natural compounds. The objective of this study was to assess the chemical characterization and microbiological potential of the essential oil Piper arboreum (EOPa) to provide data to enable the development of a low-cost mouthwash. The evaluation of the antibacterial and bacterial resistance modulating activity was performed by the microdilution method to determine the minimum inhibitory concentration. The chemical components were characterized by gas chromatography coupled with mass spectrometry, which identified 20 chemical constituents, with caryophyllene oxide being one of the major compounds. The EOPa showed an MIC ≥ 1024 µg/mL for all bacterial strains used in the tests. When evaluating the modulating activity of EOPa combined with chlorhexidine, mouthwash and antibiotics against the bacterial resistance, the oil limited synergistic activity between the MIC of the products tested in combination (37% to 87.5%). Therefore, we recommend expanding the tests with greater variation in the EOPa concentration and the products used, as well as toxicity assessments and in vivo testing, with the purpose of the development of a possible low-cost mouthwash base that is accessible to the most vulnerable populations.

The 1,8-naphthyridines sulfonamides are NorA efflux pump inhibitors.

OBJECTIVE: Efflux pumps are transmembrane proteins associated with bacterial resistance mechanisms. Bacteria use these proteins to actively transport antibiotics to the extracellular medium, preventing the pharmacological action of these drugs. This study aimed to evaluate in vitro the antibacterial activity of 1,8-naphthyridines sulfonamides, as well as their ability to inhibit efflux systems of Staphylococcus aureus strains expressing different levels of the NorA efflux pump. METHODS: The broth microdilution test was performed to assess antibacterial activity. Efflux pump inhibition was evaluated in silico by molecular docking and in vitro by fluorometric tests, and the minimum inhibitory concentration (MIC) was determined. The MIC was determined in the association between 1,8-naphthyridine and norfloxacin or ethidium bromide. RESULTS: The 1,8-naphthyridines did not show direct antibacterial activity. However, they effectively reduced the MIC of multidrug-resistant bacteria by associating with norfloxacin and ethidium bromide, in addition to increasing the fluorescence emission. In silico analysis addressing the binding between NorA and 1,8-naphthyridines suggests that hydrogen bonds and hydrophilic interactions represent the interactions with the most favourable binding energy, corroborating the experimental data. CONCLUSION: Our data suggest that 1,8-naphthyridines sulfonamides inhibit bacterial resistance through molecular mechanisms associated with inhibition of the NorA efflux pump in S. aureus strains.

Gênero Acosmium: composição química e potencial farmacológico: [revisão] / Acosmium genus: chemical composition and pharmacological potential: [review]

O gênero Acosmium possui 17 espécies com distribuição geográfica que se estende do sudeste do México até o Nordeste da Argentina, sendo que a maioria das espécies está localizada no Brasil. A. dasycarpum, A. panamense, A. subelegans são as espécies mais utilizadas popularmente no tratamento de enfermidades. Uma busca na literatura, resguardando aspectos químicos e farmacológicos destas plantas, indicam atividade citotóxica, ação antitérmica, efeito hipoglicêmico, bem como tem sido usada no tratamento da doença de Alzheimer e desordens no sistema nervoso central. Investigação fitoquímica resultou principalmente no isolamento de terpenos, ácido cafêico, alcalóides do tipo diaza-adamantano e quinolizidínicos bem como pironas.

The genus Acosmium is composed by c.a. 17 species, with geographic distribution from southeastern Mexico to Northwestern Argentina. Most of the species, however, are located in Brazil. A. dasycarpum, A. panamense, A. subelegans are used in folk medicine to treat several ailments. A search in the literature regarding the chemical and pharmacological aspects of these plants indicates cytotoxic activity, antithermal and hypoglycemic effects, as well as their use to treat Alzheimer's disease and CNS disorders. Phytochemical investigations resulted mainly in the isolation of terpenes, caffeic acid, diaza-adamantane and quinolizidines alkaloids as well as pyrones.