Contribution of Amphipathicity and Hydrophobicity to the Antimicrobial Activity and Cytotoxicity of β-Hairpin Peptides

Abstract

Bacteria have acquired extensive resistance mechanisms to protect themselves against antibiotic action. Today the bacterial membrane has become one of the “final frontiers” in the search for new compounds acting on novel targets to address the threat of multi-drug resistant (MDR) and XDR bacterial pathogens. β-Hairpin antimicrobial peptides are amphipathic, membrane-binding antibiotics that exhibit a broad range of activities against Gram-positive, Gram-negative, and fungal pathogens. However, most members of the class also possess adverse cytotoxicity and hemolytic activity that preclude their development as candidate antimicrobials. We examined peptide hydrophobicity, amphipathicity, and structure to better dissect and understand the correlation between antimicrobial activity and toxicity, membrane binding, and membrane permeability. The hydrophobicity, pI, net charge at physiological pH, and amphipathic moment for the β-hairpin antimicrobial peptides tachyplesin-1, polyphemusin-1, protegrin-1, gomesin, arenicin-3, and thanatin were determined and correlated with key antimicrobial activity and toxicity data. These included antimicrobial activity against five key bacterial pathogens and two fungi, cytotoxicity against human cell lines, and hemolytic activity in human erythrocytes. Observed antimicrobial activity trends correlated with compound amphipathicity and, to a lesser extent, with overall hydrophobicity. Antimicrobial activity increased with amphipathicity, but unfortunately so did toxicity. Of note, tachyplesin-1 was found to be 8-fold more amphipathic than gomesin. These analyses identify tachyplesin-1 as a promising scaffold for rational design and synthetic optimization toward an antibiotic candidate.

Simplified, serine‐rich theta‐defensin analogues as antitumour peptides

“…This suggests that in terms of antitumour activity positive charge is more important than hydrophobicity value. Similar relationship is observed for antimicrobial activity of HDPs . Ala analogues contrary to Ser analogues did not exhibit activity against mammalian cells.…”

“…Cationic HDPs activity mechanism involves membrane destabilization which depends on hydrophobicity and charge of peptides . In interaction with mammalian cell membranes, hydrophobicity is the key component . Therefore, we have introduced mentioned modifications to create compounds with different hydrophobicity values (Table ).…”

Large scale ab initio modeling of structurally uncharacterized antimicrobial peptides reveals known and novel folds

“…Quantitative structure‐activity relationship (QSAR), Regression models and Machine Learning approaches such as Artificial Neural Network (ANN), Support Vector Machine (SVM), Random Forests (RF) and Hidden Markov Models (HMM) are some of the approaches employed . However, most of these studies are sequence‐based, and design efforts based on the structural properties of more complex folds, such as studies on β‐hairpins by Edwards et al or Yang et al, are less common. Notably, sequence information on its own is not sufficient to determine relevant properties of folds, such as the amphipathicity or dipole moment of the molecule.…”

Linear Thanatin Is an Effective Antimicrobial Peptide against Colistin-Resistant <i>Escherichia coli in Vitro</i>

“…Thanatin has drawn considerable interest for its satisfactory activity against MDR gram-negative bacteria [16] [17] [18]. Furthermore, it is comparatively safe for the low hemolytic and cytotoxic activity [19]. Intriguingly, the linear thanatin analogue (L-thanatin) without disulfide bond has been shown to have similar activity against extended-spectrum-β-lactamase (ESBL)-producing Escherichia coli [20].…”