Lipidation of Antimicrobial Peptides as a Design Strategy for Future Alternatives to Antibiotics

Abstract

Multi-drug-resistant bacteria are becoming more prevalent, and treating these bacteria is becoming a global concern. One alternative approach to combat bacterial resistance is to use antimicrobial (AMPs) or host-defense peptides (HDPs) because they possess broad-spectrum activity, function in a variety of ways, and lead to minimal resistance. However, the therapeutic efficacy of HDPs is limited by a number of factors, including systemic toxicity, rapid degradation, and low bioavailability. One approach to circumvent these issues is to use lipidation, i.e., the attachment of one or more fatty acid chains to the amine groups of the N-terminus or a lysine residue of an HDP. In this review, we examined lipidated analogs of 66 different HDPs reported in the literature to determine: (i) whether there is a link between acyl chain length and antibacterial activity; (ii) whether the charge and (iii) the hydrophobicity of the HDP play a role; and (iv) whether acyl chain length and toxicity are related. Overall, the analysis suggests that lipidated HDPs with improved activity over the nonlipidated counterpart had acyl chain lengths of 8–12 carbons. Moreover, active lipidated peptides attached to short HDPs tended to have longer acyl chain lengths. Neither the charge of the parent HDP nor the percent hydrophobicity of the peptide had an apparent significant impact on the antibacterial activity. Finally, the relationship between acyl chain length and toxicity was difficult to determine due to the fact that toxicity is quantified in different ways. The impact of these trends, as well as combined strategies such as the incorporation of d- and non-natural amino acids or alternative approaches, will be discussed in light of how lipidation may play a role in the future development of antimicrobial peptide-based alternatives to current therapeutics.

Effects of Lipidation on a Proline-Rich Antibacterial Peptide

“…Bac-C12 and, more significantly, Bac-Lp-I began to reduce cell viability of keratinocytes at 2–4 lower concentrations than the peptide alone. This result was quite expected, since the introduction of an alkyl chain into antimicrobial peptides often enhances the cytotoxic effects [ 48 ]. On the other hand, the difference in cytotoxicity between Bac-C12 and Bac-Lp-I was not obvious.…”

“…On the other hand, the difference in cytotoxicity between Bac-C12 and Bac-Lp-I was not obvious. It was generally observed that the cytotoxicity of lipopeptides increases with the length of their hydrophobic chain [ 48 ]. The tryptophan residue present in Lp-I and the linker used to link Bac7(1-16) and Lp-I contribute to increase the hydrophobicity of the molecule, perhaps making it more cytotoxic compared to Bac-C12.…”

“…It remains unclear what properties the peptide moiety in lipopeptides should have to optimize their activity. To date, it has not been possible to draw general lines and predict the behavior of antimicrobial lipopeptides, as these molecules can show very different effects due to the abundance of factors to be considered [ 48 ]. For example, in the work of Grimsey and colleagues, the same C-terminal lipidation process with a C-12 chain that improved the antimicrobial efficacy of one peptide was detrimental to another [ 49 ].…”

Biological and Physico-Chemical Characteristics of Arginine-Rich Peptide Gemini Surfactants with Lysine and Cystine Spacers

“…They can be both biosynthesized by microorganisms or obtained through chemical synthesis. In fact, the conjugation of a fatty acid chain to a peptide was found to be a convenient tool for obtaining molecules with improved antimicrobial activity [ 1 ]. A promising group of compounds are ultrashort cationic lipopeptides (USCLs).…”

A Chimeric Cationic Peptide Composed of Human β-Defensin 3 and Human β-Defensin 4 Exhibits Improved Antibacterial Activity and Salt Resistance

“…hBDs have been isolated from various human tissues, such as the skin, oral and nasal mucosa, lungs, salivary glands, intestines, stomach, kidney, and eyes (Garcia et al, 2001;Nitschkea et al, 2002;Eckmann, 2006). The hBDs exhibit broad-spectrum antibacterial and antiviral activity (Kalenik et al, 2018;Meade and O'Farrelly, 2018;Koeninger et al, 2020;Rodriguez et al, 2020;Rounds and Straus, 2020).…”