The Trp-rich Antimicrobial Amphiphiles With Intramolecular Aromatic Interactions for the Treatment of Bacterial Infection

Abstract

Antibiotic resistance is emerging as a hot issue with the abuse and overuse of antibiotics, and the shortage of effective antimicrobial agents against multidrug resistant bacteria creates a huge problem to treat the threatening nosocomial skin and soft tissue infection. Antimicrobial peptides (AMPs) exhibite enormous potential as one of the most promising candidates of antibiotic to fight against pathogenic infections because of its unique membrane penetration mechanism to kill pathogens, whereas the clinical application of AMPs still faces the challenges of production cost, stability, safety, and design strategy. Herein, a series of Trp-rich peptides was designed following the principle of paired Trp plated at the ith and ith+4 position on the backbone of peptides, based on the template (VKKX)4, where X represents W, A, or L, to study the effect of intramolecular aromatic interactions on the bioactivity of AMPs. Through comparing the antimicrobial performance, hemolysis, cytotoxicity, and stability, VW5 which is equipped with the characters of direct antimicrobial efficacy (GM=1.68μM) and physical destruction of bacterial membrane (SEM and electron microscopy) stood out from the engineering peptides. VW5 also performed well in mice models, which could significantly decrease the bacterial colony (VW5 vs infection group, 12.72±2.26 vs 5.52±2.01×109CFU/abscess), the area of dermo-necrosis (VW5 vs infection group, 0.74±0.29 vs 1.86±0.98mm2) and the inflammation cytokine levels at the abscess site without causing toxicity to the skin. Overall, this study provides a strategy and template to diminish the randomness in the exploration and design of novel peptides.

Tryptophan, more than just an interfacial amino acid in the membrane activity of cationic cell-penetrating and antimicrobial peptides

“…Recently, Wang and coworkers designed a series of Trp-rich peptides based on the template (VKKX)4, to obtain paired Trp at the i and i + 4 position on the backbone of peptides (where X is W , A , or L ), and to study the effect of intramolecular aromatic interactions on the bioactivity of these AMPs (Wang et al ., 2021). The peptides contain either 2 Trp, (VKKWVKKAVKKWVKKA; VKKWVKKWVKKAVKKA), 3 Trp (VKKWVKKWVKKAVKKW; VKKWVKKWVKKWVKKA), or 4 Trp, (VKKWVKKWVKKWVKKW).…”

“…In another study, it was found again that Arg- and Trp-rich sequences (H-RRWTWWWTWRR-NH 2 and H-RRWSWWWSWRR-NH 2 ) have a broad spectrum of antimicrobial activity against Gram-negative and Gram-positive bacteria (Wang et al ., 2021). Regarding their interactions with cell wall components, the two peptides interact with both LPS and LTA, although their affinity seems to be lower than melittin.…”

Designing double-site lipidated peptide amphiphiles as potent antimicrobial biomaterials to combat multidrug-resistant bacteria

“…The cytoplasmic membrane depolarization assays were performed with the membrane potential-sensitive fluorescent dye 3,3′-dipropylthiadicarbocyanine (diSC3-5). The testing procedure is the same as described in our previous reports (Wang Z. et al, 2021). We would not go into detail here in order to avoid repetition as much as possible.…”

“…Despite the fact that AMPs have shown a promising future in overcoming antibiotic resistance, several obstacles, such as insufficient bioactivities, high toxicity, susceptibility to protease degradation, and high production costs, continue to impede AMPs' further development as commercially available drugs. Numerous strategies have been suggested to increase the antimicrobial potency and lessen the toxicity of AMPs, including template modification, minimalist de novo design, and designbased AMP libraries (Ong et al, 2014;Tan et al, 2020;Yang et al, 2020;Li et al, 2021;Wang C. et al, 2021;Wang Z. et al, 2021). Moreover, a variety of strategies have been investigated to increase the proteolytic stability of AMPs, including sequence changes, peptidomimetics, cyclization, N-methylation, PEGylation, lipidation, and glycosylation (Lai et al, 2022).…”

PL‐101‐WK, a novel tryptophan‐ and lysine‐rich peptide with antimicrobial activity against Staphylococcus aureus

“…[12] Trp with unique physicochemical properties is desired for insertion into the cell membrane. [12,13] The simultaneous usage of Trp and cationic residues has been successfully used in designing AMPs, [10,14,15] in which cation-π and Trp-Trp interactions can have a significant role in their structural stability. [16,17] Plicatamide (FFHLHFH-deΔDOPA) is a short natural AMP isolated from the blood cells of Styela plicata.…”