RESUMO
Bacterial resistance has become a problem of great concern all over the world. Gram-negative bacteria, including the Enterobacteriaceae family and Pseudomonas and Acinetobacter species, are among the leading causes of healthcare-associated infections. The rate of antibiotic resistance among these pathogens has increased dramatically in recent years, reaching a pandemic scale. The most common mechanism of resistance described for Gram-negative bacteria consists of beta-lactamase production. These enzymes hydrolyze beta-lactam antibiotics, which are among the most commonly used antimicrobial agents. As with other antibiotics, reports of bacterial resistance to these agents have increased in recent years. An alternative method for combating beta-lactamasemediated resistance has been the use of small beta-lactamase inhibitors (e.g., clavulanic acid and tazobactam), allowing the resurgence of beta-lactam antibiotics for the treatment of infections caused by beta-lactamase-producing bacteria. However, due to the beta-lactamase group's diversity, some of them present resistance to conventional beta-lactamase inhibitors. Bearing this in mind, in the last two decades, beta- lactamase inhibitor peptides have been developed as alternative adjuvants to strike back against such strains. In this review, we outline the most recent findings related to the design of beta-lactamase inhibitor peptides and their biotechnological potential.
Assuntos
Infecções Bacterianas/tratamento farmacológico , Farmacorresistência Bacteriana , Peptídeos/farmacologia , Inibidores de beta-Lactamases/farmacologia , Humanos , beta-LactamasesRESUMO
Antibiotic-resistant infections are predicted to kill 10 million people per year by 2050, costing the global economy $100 trillion. Therefore, there is an urgent need to develop alternative technologies. We have engineered a synthetic peptide called clavanin-MO, derived from a marine tunicate antimicrobial peptide, which exhibits potent antimicrobial and immunomodulatory properties both in vitro and in vivo. The peptide effectively killed a panel of representative bacterial strains, including multidrug-resistant hospital isolates. Antimicrobial activity of the peptide was demonstrated in animal models, reducing bacterial counts by six orders of magnitude, and contributing to infection clearance. In addition, clavanin-MO was capable of modulating innate immunity by stimulating leukocyte recruitment to the site of infection, and production of immune mediators GM-CSF, IFN-γ and MCP-1, while suppressing an excessive and potentially harmful inflammatory response by increasing synthesis of anti-inflammatory cytokines such as IL-10 and repressing the levels of pro-inflammatory cytokines IL-12 and TNF-α. Finally, treatment with the peptide protected mice against otherwise lethal infections caused by both Gram-negative and -positive drug-resistant strains. The peptide presented here directly kills bacteria and further helps resolve infections through its immune modulatory properties. Peptide anti-infective therapeutics with combined antimicrobial and immunomodulatory properties represent a new approach to treat antibiotic-resistant infections.
Assuntos
Antibacterianos/farmacologia , Fatores Imunológicos/farmacologia , Peptídeos/farmacologia , Animais , Infecções Bacterianas/tratamento farmacológico , Proteínas Sanguíneas/farmacologia , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Imunidade Inata/efeitos dos fármacos , Imunomodulação/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Peptídeos/química , Peptídeos/uso terapêutico , Peptídeos/toxicidade , Células RAW 264.7RESUMO
Eugenia dysenterica is a plant typically found in the Cerrado biome and commonly used in popular medicine due to its pharmacological properties, which include antidiarrheal, skin healing, and antimicrobial activities. The effects of ethanolic extract, aqueous extract and infusion of E. dysenterica leaves on intestinal motility and antidiarrheal activity were evaluated using ricin oil-induced diarrhea in rats. At doses of 400 and 800 mg·Kg(-1), the ethanolic extract decreased intestinal motility while the other extracts showed no significant effects. Moreover, serum levels of chloride, magnesium, and phosphorus were also measured in rats. Histopathologic and enzymatic analyses were also performed to investigate any toxic effect. Animals treated with infusion, ethanolic extract, ricin oil, and loperamide presented morphological alterations in the small intestine, such as mucosa lesion, epithelial layer damage, and partial loss and/or morphological change of villi. Furthermore, the liver showed congestion and hydropic degeneration. Serum levels of alanine aminotransferase increased significantly in all treatments, but none rose above reference values. In summary, our results suggest that compounds present in leaves of E. dysenterica may have therapeutic benefits on recovery from diarrhea despite their toxic effects.
RESUMO
Plants have contributed over the years to the discovery of various pharmacological products. Amongst the enormous diversity of herbs with remarkable medicinal use and further pharmacological potential, here in this report we evaluated pulp extracts from Eugenia dysenterica fruits and further identified the active principle involved in such laxative activity in rats. For protein isolation, fruits were macerated with an extraction solution following precipitation with (NH(4))(2)SO(4) (100%). After dialysis, the peptide was applied onto a reversed-phase semi-preparative HPLC column, and the major fraction was eluted with 26% and 66% acetonitrile. The evaluation of molecular masses by MALDI-TOF and Tris/Tricine SDS-PAGE of HPLC fractions showed the presence of a major peptide with approximately 7 kDa. The N-terminal amino acid peptide sequence was determined and showed no similarity to other proteins deposited in the Data Bank. Peptide from E. dysenterica was able to enhance rats' intestinal motility by approximately 20.8%, probably being responsible for laxative activity. Moreover, these proteins were non-toxic to mammals, as observed in histopathology and hemolytic analyses. In conclusion, results here reported indicate that, in the near future, proteins synthesized by E. dysenterica fruits could be utilized in the development of novel biotechnological pharmaceutics with laxative properties for use in chronic constipation and irritable bowel syndrome treatment.