What is it about?
Antimicrobial peptides (AMPs) are expressed in the respiratory tract and act as effector substances of the innate immune system. A variety of cells synthesize and secrete AMPs including epithelial and professional host defense cells such as neutrophils, macrophages, and NK cells. In the human lung, beta-defensins originate from epithelial cells, macrophages and lymphocytes. alpha-defensins are synthesized by neutrophils. LL-37/hCAP-18 is produced by epithelial cells, neutrophils, lymphocytes, and macrophages. AMPs act as endogenous antibiotics by direct destruction of microorganisms. Recently, it became clear that AMPs bind to cellular receptors and activate a variety of cell types such as airway epithelial cells, endothelial cells, mast cells, macrophages, dendritic cells, and neutrophils amongst others. Concentrations of AMPs in lung secretions are altered in several pulmonary diseases.
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Why is it important?
Respiratory infections are a major clinical problem, and treatment is increasingly complicated by the emergence of microbial antibiotic resistance. Development of new antibiotics is notoriously costly and slow; therefore, alternative strategies are needed. Antimicrobial peptides, central effector molecules of the immune system, are being considered as alternatives to conventional antibiotics. These peptides display a range of activities, including not only direct antimicrobial activity, but also immunomodulation and wound repair. In the lung, airway epithelial cells and neutrophils in particular contribute to their synthesis. The relevance of antimicrobial peptides for host defense against infection has been demonstrated in animal models and is supported by observations in patient studies, showing altered expression and/or unfavorable circumstances for their action in a variety of lung diseases. Importantly, antimicrobial peptides are active against microorganisms that are resistant against conventional antibiotics, including multidrug-resistant bacteria. Several strategies have been proposed to use these peptides in the treatment of infections, including direct administration of antimicrobial peptides, enhancement of their local production, and creation of more favorable circumstances for their action.
Perspectives
AMPs probably represent the best option for the treatment of multi-drug resistant infections. Considerable effort has been expended in this area with progress and a number of AMP/peptidomimetics are in different phases of clinical trials. Since the MIC values for most AMPs are still higher than many conventional antibiotics, the primary task is to improve the antimicrobial activity, reduce the toxicity, and improve delivery efficiency. Another promising area is the design of membrane active peptidomimetics to mimic the action of existing AMPs, which can be achieved by chemical modification of existing AMPs or using unnatural amino acids. Compared to AMPs, peptidomimetics greatly expand the molecular space of membrane active antimicrobials and have the advantages of high proteolytic stability and optimizing the hydrophobicity. However, this needs to be coupled with the more detailed understanding of the molecular and atomistic interactions between AMPs/peptidomimetics and the molecular complex of the Gram-negative membrane system.
Dr Andre S Pimentel
Pontificia Universidade Catolica do Rio de Janeiro
Read the Original
This page is a summary of: Penetration of antimicrobial peptides in a lung surfactant model, Colloids and Surfaces B Biointerfaces, July 2018, Elsevier,
DOI: 10.1016/j.colsurfb.2018.04.030.
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