Efficacy of Antimicrobial Peptoids against Mycobacterium tuberculosis

c Drug-resistant pathogens are a growing problem, and novel strategies are needed to combat this threat. Among the most significant of these resistant pathogens is Mycobacterium tuberculosis, which is an unusually difficult microbial target due to its complex membrane. Here, we design peptides for specific activity against M. tuberculosis using a combination of "database filtering" bioinformatics, protein engineering, and de novo design. Several variants of these peptides are structurally characterized to validate the design process. The designed peptides exhibit potent activity (MIC values as low as 4 M) against M. tuberculosis and also exhibit broad activity against a host of other clinically relevant pathogenic bacteria such as Gram-positive bacteria (Streptococcus) and Gram-negative bacteria (Escherichia coli). They also display excellent selectivity, with low cytotoxicity against cultured macrophages and lung epithelial cells. These first-generation antimicrobial peptides serve as a platform for the design of antibiotics and for investigating structure-activity relationships in the context of the M. tuberculosis membrane. The antimicrobial peptide design strategy is expected to be generalizable for any pathogen for which an activity database can be created.

mentioning

confidence: 99%

Combined Bioinformatic and Rational Design Approach To Develop Antimicrobial Peptides against Mycobacterium tuberculosis

Pearson¹,

Kloos

Murray³

et al. 2016

“…It is noteworthy that the mycolic acid outer layer provides a wax-like architecture to the cell wall that can hinder the uptake of many antimycobacterial drugs (24). Specific features of the antimicrobial peptides and proteins (AMPs), such as low molecular weight, high cationicity, amphipathic structure, and selective affinity to the prokaryotic negatively charged cell envelope, together with their immunomodulatory effects and diverse modes of action (25), make them an interesting source of novel antimycobacterial agents (11,26). In our laboratory, we are working on the mechanism of action of two human RNases that are secreted by key effector innate cells, which are known to contribute to the host response to mycobacterial infection (12,15,27,28), and therefore sought to test their potential antimycobacterial activities.…”

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confidence: 99%

Two Human Host Defense Ribonucleases against Mycobacteria, the Eosinophil Cationic Protein (RNase 3) and RNase 7

Pulido

Torrent

Andreu

et al. 2013

There is an urgent need to develop new agents against mycobacterial infections, such as tuberculosis and other respiratory tract or skin affections. In this study, we have tested two human antimicrobial RNases against mycobacteria. RNase 3, also called the eosinophil cationic protein, and RNase 7 are two small cationic proteins secreted by innate cells during host defense. Both proteins are induced upon infection displaying a wide range of antipathogen activities. In particular, they are released by leukocytes and epithelial cells, contributing to tissue protection. Here, the two RNases have been proven effective against Mycobacterium vaccae at a low micromolar level. High bactericidal activity correlated with their bacterial membrane depolarization and permeabilization activities. Further analysis on both protein-derived peptides identified for RNase 3 an N-terminus fragment that is even more active than the parental protein. Also, a potent bacterial agglutinating activity was unique to RNase 3 and its derived peptide. The particular biophysical properties of the RNase 3 active peptide are envisaged as a suitable reference for the development of novel antimycobacterial drugs. The results support the contribution of secreted RNases to the host immune response against mycobacteria.

“…Therefore, we have developed mimics of AMPs using peptoids (poly-N-substituted glycines), which are protease-resistant (15) isomers of peptides ( Fig. 1) with broad-spectrum antibacterial activity comparable to, and in some cases better than, that of antimicrobial peptides (4,5,11,12,19).…”

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confidence: 99%

Functional Synergy between Antimicrobial Peptoids and Peptides against Gram-Negative Bacteria

Chongsiriwatana

Wetzler

Barron

2011

Self Cite

Antimicrobial peptides (AMPs) are integral components of innate immunity and are typically found in combinations in which they can synergize for broader-spectrum or more potent activity. Previously, we reported peptoid mimics of AMPs with potent and selective antimicrobial activity. Using checkerboard assays, we demonstrate that peptoids and AMPs can interact synergistically, with fractional inhibitory concentration indices as low as 0.16. These results strongly suggest that antimicrobial peptoids and peptides are functionally and mechanistically analogous.