Terpenes as bacterial efflux pump inhibitors: A systematic review.

Managing antibiotic resistance is a significant challenge in modern pharmacotherapy. While molecular analyses have identified efflux pump expression as an essential mechanism underlying multidrug resistance, the targeted drug development has occurred slower. Thus, considering the verification that terpenes can enhance the activity of antibiotics against resistant bacteria, the present study gathered evidence pointing to these natural compounds as bacterial efflux pump inhibitors. A systematic search for manuscripts published between January 2007 and January 2022 was carried out using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol and the following search terms: "Terpene"; AND "Efflux pump"; and "Bacteria." From a total of 101 articles found in the initial search, 41 were included in this review. Seventy-five different terpenes, 63 bacterial strains, and 22 different efflux pumps were reported, with carvacrol, Staphylococcus aureus SA-1199B, and NorA appearing most frequently mentioned terpene, bacterial strain, and efflux pump (EP), respectively. The Chi-Squared analysis indicated that terpenes are significantly effective EP inhibitors in Gram-positive and Gram-negative strains, with the inhibitory frequency significantly higher in Gram-positive strains. The results of the present review suggest that terpenes are significant efflux pump inhibitors and, as such, can be used in drug development targeting the combat of antibacterial resistance.

Liposome evaluation in inhibiting pump efflux of NorA of Staphylococcus aureus.

Liposomes, in addition to providing greater efficacy to antibiotics, decrease toxicity and increase selectivity. This work has as main objectives the sensitization of the need to solve bacterial resistance to antibiotics, addressing the potential of antibiotics carried by liposome. In the preparation of the liposomes, the lipids dipalmitoyl phosphatidylcholine (DPPC), dipalmitoyl phosphatidylserine (DPPS), and cholesterol (COL) with > 99% purity were used. The Staphylococcus aureus strains used were SA-1199B, which expresses the NorA gene encoding the NorA efflux protein, which expels hydrophilic fluoroquinolones and other drugs intercalating DNA dyes, and the wild strain SA-1199. The liposomes associated with antibiotics in the wild type of strain SA-1199 and the carrier strain of pump 1199B, had a better representation of growth inhibition than the wild type strain SA-1199. Given the potential for inhibition of efflux pump seen in the results, we highlight the creation of new drugs or alteration of existing drugs. They are not recognized by the efflux pumps and removed from the target cell.

Ferulic acid derivatives inhibiting Staphylococcus aureus tetK and MsrA efflux pumps.

Background: Bacterial resistance to multiple drugs has recently emerged as a serious health problem. Concomitantly, the characterization of new substances with potential antimicrobial activity has been less frequent in the drug development industry. The overexpression of genes encoding efflux pumps that expel antimicrobial drugs from the intracellular environment, lowering these to subinhibitory concentrations, are among the resistance mechanisms predisposing microorganisms to high drug resistance. Staphylococcus aureus is a bacterium found in the normal microbiota of the skin and mucous membranes, and is an opportunistic microorganism capable of causing infections with high rates of morbidity and mortality. TetK is an efflux pump characterized by its ability to provide bacterial resistance to antibiotics from the tetracycline class. This study aimed to evaluate the inhibitory effect of ferulic acid and four of its esterified derivatives against resistant Staphylococcus aureus strains. Method: Ferulic acid derivatives were obtained by esterification and then characterized by hydrogen and carbon-13 nuclear magnetic resonance analysis. The minimum inhibitory concentrations (MIC) of ferulic acid and its esterified derivatives, ethidium bromide, and antibiotics were obtained using the microdilution test, while the efflux pump inhibition test was conducted by examining reduction in the MICs. Results: Propylferulate was seen to reduce the minimum inhibitory concentration (MIC) of both the control substance ethidium bromide and the tested antibiotic, indicating that this compound is promising for the use of efflux pump inhibition of IS-58 strains. Conclusions: This study provides strong evidence that the molecular basis for this activity is potentially due to the MsrA and TetK efflux pumps. However, further investigations are necessary to prove this hypothesis and elucidate the potentiating mechanism of the modulatory effect.

Aminophenyl chalcones potentiating antibiotic activity and inhibiting bacterial efflux pump.

Chalcones and their derivatives are substances of great interest for medicinal chemistry due to their antibacterial activities. As the bacterial resistance to clinically available antibiotics has become a worldwide public health problem, it is essential to search for compounds capable of reverting the bacterial resistance. As a possibility, the chalcone class could be an interesting answer to this problem. The chalcones (2E)-1-(4'-aminophenyl)-3-(phenyl)­prop-2-en-1-one (APCHAL), and (2E)-1-(4'-aminophenyl)-3-(4-chlorophenyl)­prop-2-en-1-one (ACLOPHENYL) were synthesized by the Claisen-Schmidt condensation and characterized by 1H and 13C nuclear magnetic resonance (NMR), Fourier-transform infrared (FT-IR), and mass spectrometry (MS), In addition, microbiological tests were performed to investigate the antibacterial activity, modulatory potential, and efflux pump inhibition against Staphylococcus aureus (S. aureus) multi-resistant strains. Regarding the S. aureus Gram-positive model, the APCHAL presented synergism with gentamicin and antagonism with penicillin. APCHAL reduced the Minimum inhibitory concentration (MIC) of gentamicin by almost 70%. When comparing the effects of the antibiotic modifying activity of ACLOPHENYL and APCHAL, a loss of synergism is noted with gentamicin due to the addition of a chlorine to the substance structure. For Escherichia coli (E. coli) a total lack of effect, synergistic or antagonistic, was observed between ACLOPHENYL and the antibiotics. In the evaluation of inhibition of the efflux pump, both chalcones presented a synergistic effect with norfloxacin and ciprofloxacin against S. aureus, although the effect is much less pronounced with ACLOPHENYL. The effect of APCHAL is particularly notable against the K2068 (MepA overexpresser) strain, with synergistic effects with both ciprofloxacin and ethidium bromide. The docking results also show that both compounds bind to roughly the same region of the binding site of 1199B (NorA overexpresser), and that this region overlaps with the preferred binding region of norfloxacin. The APCHAL chalcone may contribute to the prevention or treatment of infectious diseases caused by multidrug-resistant S. aureus.