The Potential of Modified and Multimeric Antimicrobial Peptide Materials as Superbug Killers

Abstract

Antimicrobial peptides (AMPs) are found in nearly all living organisms, show broad spectrum antibacterial activity, and can modulate the immune system. Furthermore, they have a very low level of resistance induction in bacteria, which makes them an ideal target for drug development and for targeting multi-drug resistant bacteria ‘Superbugs’. Despite this promise, AMP therapeutic use is hampered as typically they are toxic to mammalian cells, less active under physiological conditions and are susceptible to proteolytic degradation. Research has focused on addressing these limitations by modifying natural AMP sequences by including e.g., d-amino acids and N-terminal and amino acid side chain modifications to alter structure, hydrophobicity, amphipathicity, and charge of the AMP to improve antimicrobial activity and specificity and at the same time reduce mammalian cell toxicity. Recently, multimerisation (dimers, oligomer conjugates, dendrimers, polymers and self-assembly) of natural and modified AMPs has further been used to address these limitations and has created compounds that have improved activity and biocompatibility compared to their linear counterparts. This review investigates how modifying and multimerising AMPs impacts their activity against bacteria in planktonic and biofilm states of growth.

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

“…Indeed, many AMPs containing Trp residues have substantial antibacterial activity, in which the number and position of Trps are major influential factors. [9,10,48] Overall, the antibacterial activity of PL-101-WK was in agreement with the prediction of CAMP R3 . Furthermore, the less antibacterial activity of PL-101 can be anticipated by its lower instability index compared to PL-101-WK.…”

“…[3] Cationicity and hydrophobicity are essential factors in the function of AMPs. [9] The cationic residues of AMPs take a role in electrostatic interaction with a negatively-charged bacterial membrane. [9][10][11] Among hydrophobic amino acids, tryptophan (Trp) can be seen in over 25% of short AMPs.…”

Important Roles and Potential Uses of Natural and Synthetic Antimicrobial Peptides (AMPs) in Oral Diseases: Cavity, Periodontal Disease, and Thrush

“…The current limitations of natural and modified AMPs can be overcome by multimerization to design compounds with improved activity and biocompatibility. This subject is beyond the scope of this review but it is available in the literature [ 71 , 219 ]. Another important topic is the use of advanced drug delivery systems (DDSs) to allow AMPs for oral administration.…”

“… Electrostatic interactions between cationic peptides with amphophilic/amphipathic properties and negatively charged cell membranes [ 70 ]. ( a ) Barrel-stave model, ( b ) carpet model and ( c ) toroidal model [ 71 ]. The hydrophilic region effects the spot-on peptide alignment on the bacterial membrane [ 71 ].…”

“…( a ) Barrel-stave model, ( b ) carpet model and ( c ) toroidal model [ 71 ]. The hydrophilic region effects the spot-on peptide alignment on the bacterial membrane [ 71 ]. The figure is reproduced from Ref.…”