Antibiotic immunotherapy
An antibiotic sewn to a chemoattractant helps fight resistant staphylococcus
Yulia Panchenko, PCR.news
Scientists from Australia and the USA covalently linked the antibiotic vancomycin and a chemoattractant to combat methicillin-resistant strains of Staphylococcus aureus. Vancomycin binds to the bacterial cell wall, and chemoattractant binds to receptors on the surface of neutrophils. The authors demonstrated the effectiveness of this compound on microfluidic chips and in vivo on a mouse model of bacterial pneumonia.
Phagocytosis of bacteria Staphylococcus aureus (red) neutrophils (blue).
The resistance of bacteria to antibiotics is becoming an increasing problem. So, methicillin-resistant strains Staphylococcus aureus is responsible for 37% of all cases of infection with Staphylococcus aureus. In addition, S. aureus has a number of secreted factors that help it evade the action of the immune system. Scientists from Australia and the USA have tested a new strategy to combat antibiotic-resistant bacteria. To do this, they covalently combined a chemoattractant and an antibiotic. Formylated peptides (fPep) were used as a chemoattractant, which interact with receptors on the surface of immune cells and stimulate chemotaxis and phagocytosis of bacteria. The authors chose the antibiotic vancomycin, which targets S. aureus and binds to its cell wall.
Scientists have found that covalent attachment of a chemoattractant to an antibiotic can reduce the activity of the latter. They optimized the linking site to reduce this effect. It was not possible to completely get rid of it, but the authors were more important than the ability of vancomycin to target S. aureus, including its antibiotic-resistant strains. The fPep sequence was also optimized so that they attract neutrophils as efficiently as possible. To do this, we created a peptide library based on the fMLFG sequence.
To test the effectiveness of the created compounds, scientists used a microfluidic chip. Almost immediately after the start of the experiment, neutrophil chemotaxis was detected, and fluorescence indicating bacterial phagocytosis began after 60 minutes. The authors showed that the compounds controlled the growth of S. aureus better than fPep or vancomycin by themselves, and conjugates bound to the cell wall of Staphylococcus.
The fPep-vancomycin conjugate interacts with the main receptors of formylated peptides on the surface of neutrophils — FPR1 and FPR2, but more strongly with FPR2. At the same time, free fpeps are preferably bound to FPR1.
The effect of the most effective compound was tested on a mouse model of pneumonia caused by methicillin-resistant S. aureus. 12 hours after therapy, a significant decrease in bacterial load in the lungs was shown. The effect was stronger than after using a single vancomycin. When the antibiotic was administered, inflammation in the lungs was weaker than in control mice, and when the conjugate was administered, it was even weaker. Bacterial load was also lowest in the group that received fPep-vancomycin.
Thus, the authors have shown the effectiveness of antibacterial therapy with antibiotic-chemoattractant compounds. They prevent Staphylococcus aureus from escaping the action of the immune system. Scientists note that so far their attention has been focused on neutrophils, but formylated peptide receptors are also present on the surface of macrophages, monocytes and dendritic cells.
Article by Payne et al. Antibiotic-chemoattractants enhance neutrophil clearance of Staphylococcus aureus is published in the journal Nature Communications.
Portal "Eternal youth" http://vechnayamolodost.ru