With the advent of antibiotics, bacterial infections were supposed to be a thing of past. However, this instead led to the selection and evolution of bacteria with mechanisms to counter the action of antibiotics. Antibiotic efflux is one of the major mechanisms, whereby bacteria pump out the antibiotics from their cellular interior to the external environment using special transporter proteins called efflux pumps. Inhibiting these pumps seems to be an attractive strategy at a time when novel antibiotic supplies are dwindling. Molecules capable of inhibiting these pumps, known as efflux pump inhibitors (EPIs), have been viewed as potential therapeutic agents that can rejuvenate the activity of antibiotics that are no longer effective against bacterial pathogens. EPIs follow some general mechanisms of efflux inhibition and are derived from various natural as well as synthetic sources. This review focuses on EPIs and identifies the challenges that have kept these futuristic therapeutics away from the commercial realm so far.

Efflux pump inhibitors for bacterial pathogens: From bench to bedside.

Excessive use of antibiotics has led to the emergence of multidrug-resistant bacteria that are a serious threat to human health. There is a need to develop efficient antibacterial agents to address this problem. Tannins are high molecular weight (MW) polyphenols (500−30,000 Da), distributed throughout the plant kingdom. Tannins are one of the major compounds in plants with potential health benefits. This review addresses the antibacterial and antivirulence effects of different types of tannins and highlights the underlying antibacterial mechanisms of action. Furthermore, an overview of the antibacterial effects of emerging tannin-loaded nanoparticles/hydrogels is presented. Tannins have been found to inhibit bacterial growth using different mechanisms of action including iron chelation, inhibition of cell wall synthesis, disruption of the cell membrane, and inhibition of fatty acid biosynthetic pathways. Tannins can act as quorum sensing inhibitors and attenuate the gene expression of several virulence factors such as biofilms, enzymes, adhesins, motility, and toxins. Also, tannin-loaded nanoparticles/hydrogels show good antibacterial effects. Overall, tannins may be promising antibacterial and antivirulence agents for preventing bacterial infections.

Tannins as an alternative to antibiotics

The widespread use of antibiotics has caused the rapid emergence of antibiotic-resistant bacterial strains and antibiotic resistance genes in the past few decades Photocatalytic inactivation, a promising approach for the killing of pathogens, efficiently avoids the problems induced by antimicrobial drugs However, traditional photocatalysts usually have some disadvantages, such as high costs of raw materials, ultraviolet ray excitation, and potential leaching of toxic metals Here, a metal-free heterojunction photocatalyst, denoted as CQDs/g-C3 N4 , is synthesized through incorporating carbon quantum dots (CQDs) on graphitic carbon nitride (g-C3 N4 ), which significantly enhances photocatalytic inactivation of Staphylococcus aureus (S aureus) compared with pure g-C3 N4 in vitro CQDs/g-C3 N4 causes a rapid increase of intracellular reactive oxygen species levels and destruction of cell membranes under visible light, eventually leading to death of bacteria The efficacy of CQDs/g-C3 N4 is further examined by a mouse cutaneous infection model of S aureus CQDs/g-C3 N4 markedly reduces the bacterial loads and prompts lesion recovery in mice, as compared with g-C3 N4 -treated group In vivo and in vitro toxicity analyses show that the side effects of CQDs/g-C3 N4 are negligible Considering the efficient photocatalytic inactivation and nontoxicity of CQDs/g-C3 N4 , this visible-light-driven photocatalyst paves a brand new avenue for the treatment of S aureus infection

Nontoxic Carbon Quantum Dots/g-C 3 N 4 for Efficient Photocatalytic Inactivation of Staphylococcus aureus under Visible Light

Background: The emergence of multidrug-resistant organisms (MDROs) is a global public health issue, severely hindering clinicians in administering appropriate antimicrobial therapy. Drug repurposing is a drug development strategy, during which new pharmacological applications are identified for already approved drugs. From the viewpoint of the development of virulence inhibitors, inhibition of quorum sensing (QS) is a promising route because various important features in bacterial physiology and virulence are mediated by QS-dependent gene expression. Methods: Forty-five pharmacological agents, encompassing a wide variety of different chemical structures and mechanisms of action, were tested during our experiments. The antibacterial activity of the compounds was tested using the broth microdilution method. Screening and semi-quantitative assessment of QS-inhibition by the compounds was performed using QS-signal molecule-producing and indicator strains. Results: Fourteen pharmaceutical agents showed antibacterial activity in the tested concentration range, while eight drugs (namely 5-fluorouracil, metamizole-sodium, cisplatin, methotrexate, bleomycin, promethazine, chlorpromazine, and thioridazine) showed dose-dependent QS-inhibitory activity in the in vitro model systems applied during the experiments. Conclusions: Virulence inhibitors represent an attractive alternative strategy to combat bacterial pathogens more efficiently. Some of the tested compounds could be considered potential QS-inhibitory agents, warranting further experiments involving additional model systems to establish the extent of their efficacy.

The Role of Drug Repurposing in the Development of Novel Antimicrobial Drugs: Non-Antibiotic Pharmacological Agents as Quorum Sensing-Inhibitors.

Antimicrobial resistance is a critical health problem, and pathogens responsible for common infections have developed resistance to antimicrobials, posing a threat to global health and placing a huge burden on health services. During the past two decades, the search for new bioactive agents in nature has become extremely important for promoting health and in the development of more efficient antimicrobials. The genus Eugenia is one of the largest in the Myrtaceae family, comprising approximately 1000 species from Mexico to Argentina, with a few species distributed in Australia and Africa. Eugenia species are used in folk medicine, with antidiabetic, antirheumatic, antipyretic, anti-inflammatory, antidiarrheal, antifungal, and antibacterial properties. This study systematically reviews the Eugenia species to compile the phytochemical composition and antimicrobial effects. In addition, we provide information regarding the traditional uses and cytotoxic activity of Eugenia species. We conducted a systematic literature search of specialized databases (Web of Science, Scielo, Lilacs, Pubmed, Science Direct, Scopus) and selected articles published between 1973 and 2015 using Eugenia and antimicrobial activity, Eugenia and toxicity, and Eugenia and chemical composition as key words. Ninety-three studies were included, and the phytochemical analyses from these studies show that Eugenia species are a rich source of flavonoids, tannins, triterpenes, and sesquiterpenes. Chemical constituents play an apparent role in the antimicrobial effects and reinforce the known antimicrobial potential of the Eugenia genus. It is worth mentioning that some Eugenia species cause significant cytotoxicity.

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Traditional Uses, Phytochemistry, and Antimicrobial Activities of Eugenia Species - A Review.

Tannic acid affects the phenotype of Staphylococcus aureus resistant to tetracycline and erythromycin by inhibition of efflux pumps.

Alpha-tocopherol is one the most abundant and biologically active isoforms of vitamin E. This compound is a potent antioxidant and one of most studied isoforms of vitamin E. Vitamin D3 (cholecalciferol) is an important nutrient for calcium homeostasis and bone health, that has also been recognized as a potent modulator of the immune response. Methicillin-resistant Staphylococcus aureus (MRSA) is the most important causative agent of both nosocomial and community-acquired infections. The aim of this study was to evaluate the inhibitory effect of alpha-tocopherol and cholecalciferol on both S. aureus and multidrug resistant S. aureus efflux pumps. The RN4220 strain has the plasmid pUL5054 that is the carrier of gene that encodes the macrolide resistance protein (an efflux pump) MsrA; the IS-58 strain possesses the TetK tetracycline efflux protein in its genome and the 1199B strain resists to hydrophilic fluoroquinolones via a NorA-mediated mechanism. The antibacterial activity was evaluated by determining the Minimal Inhibitory Concentration (MIC) and a possible inhibition of efflux pumps was associated to a reduction of the MIC. In this work we observed that in the presence of the treatments there was a decrease in the MIC for the RN4220 and IS-58 strains, suggesting that the substances presented an inhibitory effect on the efflux pumps of these strains. Significant efforts have been done to identify efflux pump inhibitors (EPIs) from natural sources and, therefore, the antibacterial properties of cholecalciferol and alphatocopherol might be attributed to a direct effect on the bacterial cell depending on their amphipathic structure.

Original article: ACTION OF CHOLECALCIFEROL AND ALPHA-TOCOPHEROL ON STAPHYLOCOCCUS AUREUS EFFLUX PUMPS

Some Staphylococcus species are frequently recognized as etiological agents of many animal and human opportunistic infections. This is the first report testing the antibiotic resistance-modifying activity of Eugenia jambolanum and Eugenia uniflora against methicillin-resistant Staphylococcus aureus — MRSA strain. In this study, the ethanol extracts of Eugenia jambolanum L., Eugenia uniflora L. and chlorpromazine were tested for their antimicrobial activity alone or in combination with aminoglycosides against an MRSA strain using microdilution method. Synergism between both extracts and all aminoglycosides assayed was demonstrated, except E. jambolanum and tobramycin. In the same form, synergism was observed between chlorpromazine and kanamicin, neomycin and tobramicin, indicating the involvement of an efflux system in the resistance to these aminoglycosides. It is therefore suggested that extracts from E. uniflora L. and E. jambolanum L. could be used as a source of plant derived natural products to modif...

José P. Siqueira-Junior

Papers

Tannic acid affects the phenotype of Staphylococcus aureus resistant to tetracycline and erythromycin by inhibition of efflux pumps.

Original article: ACTION OF CHOLECALCIFEROL AND ALPHA-TOCOPHEROL ON STAPHYLOCOCCUS AUREUS EFFLUX PUMPS

Fruits to potentiate the antibiotic activity: the effect of eugenia uniflora and eugenia jambolanum l. against mrsa