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

Abstract

Rapidly evolving antimicrobial resistance and extremely slow development of new antibiotics have resulted in multidrug-resistant bacterial infections that present a serious threat to human health. Antimicrobial peptides (AMPs) provide promising substitutes, but more research is needed to address several of their present limitations, such as insufficient antimicrobial potency, high toxicity, and low stability. Here, we designed a series of novel double-site lipidated peptide amphiphiles based on a heptad repeat parent pentadecapeptide. The double-site lipidated peptide amphiphiles showed a broad spectrum of antimicrobial activities. Especially the double-site lipidated peptide amphiphile WL-C6 exhibited high potency to inhibit multidrug-resistant bacteria without significant toxicity toward mammalian cells. Furthermore, even at physiological salt ion concentrations, WL-C6 still exhibited outstanding antibacterial properties, and a sizeable fraction of it maintained its molecular integrity after being incubated with different proteases. Additionally, we captured the entire process of WL-C6 killing bacteria and showed that the rapid bacterial membrane disruption is the reason of bacterial death. Overall, WL-C6 shows great promise as a substitute for conventional antibiotics to combat the growing threat of multidrug-resistant bacterial infections.

Advances of Antimicrobial Peptide‐Based Biomaterials for the Treatment of Bacterial Infections

“…[ 17a,143 ] The AMP‐based biomaterials with high stability may be beneficial in the treatment of these biomaterials for various bacterial infections due to their conservative antimicrobial activity. [ 31,144 ] Second, most AMP‐based biomaterial design or optimization strategies mainly take in vitro antimicrobial activity and toxicity as the primary judgment criteria, while ignoring the current in vivo biocompatibility and therapeutic potential. Thus, although a large database of AMPs has been created and thousands of AMP‐based biomaterials have been modified or newly designed, their clinical translation remains restricted.…”

Engineering the interaction of short antimicrobial peptides with bacterial barriers

“…104 Interestingly, double-sited lipidated peptides were synthesized using shorter chain lengths (C2–C10) showing high antibacterial activity and lower cytotoxicity with respect to analogues with longer single lipid chains. 105 Further, bolaamphiphiles with a generic structure Arg–(Ala) x –Arg exhibited different self-association properties as a function of the number of Ala residues with correlated antimicrobial activities against both GP and GN species, thus representing a promising class of potential AMPs (Fig. 6a).…”

Molecular Mechanisms of Bacterial Resistance to Antimicrobial Peptides in the Modern Era: An Updated Review

“…For instance, lipidation involves attaching fatty acids to the active regions of the peptides [85]. The lipid addition confers numerous advantages to AMPs without altering their fundamental characteristics, such as increasing hydrophobicity, enhancing membrane interaction, improving penetrability, reducing degradation (thus increasing stability), and preserving cationic charges [86][87][88]. Nevertheless, this mechanism may also have significant drawbacks.…”