Antibiotic resistance is one of the main problems concerning public health or clinical practice. Antimicrobial peptides appear as good candidates for the development of new therapeutic drugs. In this ...study we de novo designed a group of cationic antimicrobial peptides, analyzed its physicochemical properties, including its structure by circular dichroism and studied its antimicrobial properties against a panel of clinical isolates expressing different mechanisms of resistance. Three cationic alpha helical peptides exhibited antimicrobial activity comparable to, or even better than the comparator omiganan (MBI-226).
De novo designed alpha helical cationic peptides with antimicrobial activity against multi-resistant clinical isolates. Display omitted
•De novo designed cationic peptides.•Physicochemical properties of peptides.•Antimicrobial resistant bacteria.
Cationic antimicrobial peptides (AMPs) are short linear amino acid sequences, which display antimicrobial activity against a wide range of bacterial species. They are promising novel antimicrobials ...since they have shown bactericidal effects against multiresistant bacteria. Their amphiphilic structure with hydrophobic and cationic regions drives their interaction with anionic bacterial cytoplasmic membranes, which leads to their disruption. In this work two synthetic designed AMPs, P5 and P6.2, which have been previously analyzed in their ability to interact with bacterial or eukaryotic membranes, were evaluated in their anti-biofilm and in vivo antibacterial activity. In a first step, a time-kill kinetic assay against P. aeruginosa and S. aureus and a curve for hemolytic activity were performed in order to determine the killing rate and the possible undesirable toxic effect, respectively, for both peptides. The biofilm inhibitory activity was quantified at sub MIC concentrations of the peptides and the results showed that P5 displayed antibiofilm activity on both strains while P6.2 only on S. aureus. Scanning electron microscopy (SEM) of bacteria treated with peptides at their MIC revealed protruding blisters on Gam-negative P. aeruginosa strain, but almost no visible surface alteration on Gram-positive S. aureus. These micrographs highlighted different manifestations of the membrane-disrupting activity that these kinds of peptides possess. Finally, both peptides were analyzed in vivo, in the lungs of neutropenic mice previously instilled with P. aeruginosa. Mice lungs were surgically extracted and bacteria and pro-inflammatory cytokines (IL-β, IL-6 and TNF-α) were quantified by colony forming units and ELISA, respectively. Results showed that instillation of the peptides produced a significant decrease in the number of living bacteria in the lungs, concomitant with a decrease in pro-inflammatory cytokines. Overall, the results presented here suggest that these two new peptides could be good candidates for future drug development for anti-biofilm and anti-infective therapy.
•Two novel AMPs P5 and P6.2 were analyzed in P.aeruginosa and S. aureus.•Scanning electron microscopy revealed distinct membranolytic activity.•Both peptides display in vitro antibiofilm activity.•Peptides diminished P.aeruginosa burden in the lungs of neutropenic mice.•P5 and P6.2 diminished lung pro-inflammatory cytokines.
During microbial infection, neutrophils (polymorphonuclear leukocytes; PMNs) activate dendritic cells (DCs). However, early reports illustrated that neutrophil-derived mediators may suppress ...responses to mitogens. In the present study, we investigated the mechanism used by PMNs to modulate the immunostimulatory ability of DCs. Autologous syngeneic PMNs decreased T-cell proliferation induced by allogeneic DCs. Culture supernatant (CS) derived from PMNs also decreased allostimulation ability of immature DCs and increased the expression of transforming growth factor (TGF)-β1 on DCs. A TGF-β1 monoclonal antibody, a CD40 monoclonal antibody, or a serine protease inhibitor reversed the effect of PMN CS on DC allostimulatory ability. Furthermore, elastase reproduced the inhibitory effect of PMN CS on DC allostimulatory ability and the TGF-β1 production. The role of elastase was confirmed by examining PMN CS from two patients with cyclic neutropenia, a disease due to mutations in the neutrophil elastase gene. These PMN CS samples had reduced elastase activity and were unable to increase DC TGF-β1 production. Moreover, elastase and PMN CS induced IκBα degradation in DCs. We conclude that PMNs decrease DC allostimulatory ability via production of elastase leading to a switch of immature DCs into TGF-β1-secreting cells.
, the etiologic agent of tuberculosis (TB), has killed nearly one billion people during the last two centuries. Nowadays, TB remains a major global health problem ranked among the top 10 causes of ...death worldwide. One of the main challenges in developing new strategies to fight TB is focused on reducing the duration and complexity of drug regimens. Cannabidiol (CBD) is the main nonpsychoactive ingredient extracted from the
. plant, which has been shown to be biologically active against bacteria. The purpose of this work was to investigate the antimicrobial effect of CBD on
intracellular infection.
To assess the minimum inhibitory concentration (MIC) of CBD on mycobacterial strains, the MTT assay was performed on
, and the Colony-Forming Unit (CFU) assay was conducted on
H37Rv. Additionally, the cytotoxic effect of CBD on THP-1 cells was assessed by MTT assay. Moreover, macrophages derived from the THP-1 cell were infected with
H37Rv (multiplicity of infection 1:10) to evaluate the intracellular activity of CBD by determining the CFU/mL.
Antimicrobial activity against
(MIC=100 μM) and
H37Rv (MIC=25 μM) cultures was exhibited by CBD. Furthermore, the effect of CBD was also evaluated on
H37Rv infected macrophage cells. Interestingly, a reduction in viable intracellular
H37Rv bacteria was observed after 24 h of treatment. Moreover, CBD exhibited a safe profile toward human THP-1 cells, since it showed no toxicity (CC
=1075 μM) at a concentration of antibacterial effect (selectivity index 43).
These results extend the knowledge regarding the antimicrobial activity of CBD and demonstrate its ability to kill the human intracellular pathogen
Pharmacogenetics studies how genetic variation influences the response of patients to drugs. This discipline has a greater impact in those medical specialties that treat complex diseases in which the ...therapeutic response is insufficient and/or have high costs such as psychiatry. This is a narrative review in which we analyze the main results of pharmacogenetic studies performed with the most relevant groups of psychoactive drugs and discusses missing for incorporating these advances into our daily practice. We conclude that despite the remarkable progress in the field of Pharmacogenetics in the last 10 years, studies in psychiatry have been inconclusive and the clinical use of pharmacogenetic testing is still limited. However, there are some encouraging elements about the applicability of these tools for the improvement of psychiatric treatments.
During microbial infection, neutrophils (polymorphonuclear leukocytes; PMNs) activate dendritic cells (DCs). However, early reports illustrated that neutrophil-derived mediators may suppress ...responses to mitogens. In the present study, we investigated the mechanism used by PMNs to modulate the immunostimulatory ability of DCs. Autologous syngeneic PMNs decreased T-cell proliferation induced by allogeneic DCs. Culture supernatant (CS) derived from PMNs also decreased allostimulation ability of immature DCs and increased the expression of transforming growth factor (TGF)-beta1 on DCs. A TGF-beta1 monoclonal antibody, a CD40 monoclonal antibody, or a serine protease inhibitor reversed the effect of PMN CS on DC allostimulatory ability. Furthermore, elastase reproduced the inhibitory effect of PMN CS on DC allostimulatory ability and the TGF-beta1 production. The role of elastase was confirmed by examining PMN CS from two patients with cyclic neutropenia, a disease due to mutations in the neutrophil elastase gene. These PMN CS samples had reduced elastase activity and were unable to increase DC TGF-beta1 production. Moreover, elastase and PMN CS induced IkappaBalpha degradation in DCs. We conclude that PMNs decrease DC allostimulatory ability via production of elastase leading to a switch of immature DCs into TGF-beta1-secreting cells.
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