Antimicrobial Polymer-Based Assemblies

International Journal of Molecular Sciences Review Antimicrobial Polymer−Based Assemblies: A Review Ana Maria Carmona-Ribeiro * and Péricles Marques Araújo Biocolloids Laboratory, Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Professor Lineu Prestes 748, São Paulo 05508-000, Brazil; [email protected] * Correspondence: [email protected] Abstract: An antimicrobial supramolecular assembly (ASA) is conspicuous in biomedical applications. Among the alternatives to overcome microbial resistance to antibiotics and drugs, ASAs, including antimicrobial peptides (AMPs) and polymers (APs), provide formulations with optimal antimicrobial activity and acceptable toxicity. AMPs and APs have been delivered by a variety of carriers such as nanoparticles, coatings, multilayers, hydrogels, liposomes, nanodisks, lyotropic lipid phases, nanostructured lipid carriers, etc. They have similar mechanisms of action involving adsorption to the cell wall, penetration across the cell membrane, and microbe lysis. APs, however, offer the advantage of cheap synthetic procedures, chemical stability, and improved adsorption (due to multipoint attachment to microbes), as compared to the expensive synthetic routes, poor yield, and subpar in vivo stability seen in AMPs. We review recent advances in polymer−based antimicrobial assemblies involving AMPs and APs. Keywords: cationic peptides and polymers; structure–function relationship; hydrophobic–hydrophilic balance; mechanism of cell lysis; multidrug−resistant microbes; ESKAPE pathogens; MRSA; quater- Citation: Carmona-Ribeiro, A.M.; nized biopolymers; antibiofilm and thromboresistant activity Araújo, P.M. Antimicrobial Polymer−Based Assemblies: A Review. Int. J. Mol. Sci. 2021, 22, 5424. https://doi.org/10.3390/ 1. Introduction ijms22115424 Antibiotic−resistant pathogens have been considered a major menace to humans [1] so that a variety of combinatory anti−pathogenic therapies have emerged [2–4]. Antibiotics Academic Editors: Lucia have been combined with bacteriophages [5], photodynamic light therapy yielding reactive Ya. Zakharova, Francesco Trotta and oxygen species (ROS) [6], antimicrobial peptides (AMPs) [7–9], nanoparticles (NPs), cationic Ruslan R. Kashapov antimicrobial polymers (APs), and cationic lipids assembled as bilayer disks, vesicles, or micelles [10,11]. In general, alternative/novel therapies against multidrug−resistant (MDR) Received: 4 April 2021 pathogens have shown promising in vitro results, but overcoming their in vivo drawbacks Accepted: 17 May 2021 has remained a central challenge. Figure1 illustrates some limitations in the way of Published: 21 May 2021 alternative approaches. An antimicrobial supramolecular assembly (ASA) has been opening new horizons in Publisher’s Note: MDPI stays neutral terms of allowing for optimal as well as broad antimicrobial activity [1,12–20]. Compo- with regard to jurisdictional claims in nents in ASA materials can be organic, inorganic or hybrid, acting as antibacterial agents published maps and institutional affil- − iations. themselves and/or as carriers for timed release of the antibacterial agent(s). ASA formulations have included coatings [21–24], functionalized surfaces [25,26], NPs [14,17,27–32], surfactant and/or lipid dispersions such as vesicles, liposomes, lipid disks [12,13,20,33], hydrogels [34–36], wound dressings [37], dentistry materials [38], etc. Several ASA modes of action have been described in the literature, such as leaching of Copyright: © 2021 by the authors. the antibacterial agent from the material [39], killing upon contact [25,40–44], or preventing Licensee MDPI, Basel, Switzerland. microbial adhesion [22,45,46]. Several ASA−delivered AMPs or APs act by penetrating This article is an open access article the cell wall, reaching bacterial cell membranes and causing their disruption [25,47]. distributed under the terms and conditions of the Creative Commons In this review, recent developments in ASAs employing AMPs or APs were discussed Attribution (CC BY) license (https:// in regards to their structure, activity, and applications. creativecommons.org/licenses/by/ 4.0/). Int. J. Mol. Sci. 2021, 22, 5424. https://doi.org/10.3390/ijms22115424 https://www.mdpi.com/journal/ijms Int.Int. J.J. Mol.Mol. Sci. 2021,, 22,, 5424x FOR PEER REVIEW 22 of of 2728 FigureFigure 1.1. Alternative approaches toto overcomeovercome multidrugmultidrug−−resistantresistant (MDR) (MDR) microbes microbes and their possible shortcomings. ReprintedReprinted fromfrom [[1].1]. 2. ASA with AMPs In this review, recent developments in ASAs employing AMPs or APs were dis- 2.1. Structure and Antimicrobial Activity of ASA with AMPs cussed in regards to their structure, activity, and applications. AMPs have been considered as amphipathic, cationic polymers with less than 50 amino2. ASA acid with residues, AMPs often displaying secondary structures such as α−helix [7–9,48]. Their main role in the innate immune system as an indispensable line of defense against pathogens 2.1. Structure and Antimicrobial Activity of ASA with AMPs in different body parts of mammals, plants, and other animals has been well documented [9]. In humans,AMPs AMPshave been present considered in oral and as nasal amphipathic, mucosae couldcationic activate polymers anti− inflammatorywith less than cells 50 toamino sites acid of damaged residues, tissueoften displaying [49]. In fish, secondary constant structures exposure tosuch various as α−helix types [7–9,48]. of pathogens Their hasmain led role to anin immunethe innate system immune based system on AMPs as an [50 indispensable]. The cationic line character of defense determined against AMPs’pathogens interactions in different with body the oppositely parts of mammals charged bacteria, plants, cell and wall other and animals penetration has been in the well cell membrane.documented Destabilization [9]. In humans, of theAMPs membrane present electrochemical in oral and nasal potential mucosae allowed could AMP activate insertion an- inti−inflammatory the plasmatic membranecells to sites of of the damaged bacteria, tissue its rupture [49]. In and fish, bacterial constant cell exposure death [to7, 9various,51,52]. Majortypes issuesof pathogens against AMPshas led applications to an immune have beensystem related based to on AMPs’ AMPs toxicity [50]. toThe eukaryotic cationic cells,character poor determined stability in vivoAMPs’with interactions eventual degradation with the oppositely during transportation charged bacteria to their cell target wall cellsand penetration and organs [in32 the,51, 53cell,54 membrane.]. Destabilization of the membrane electrochemical potentialAMPs allowed have been AMP classified insertion according in the plasmatic to their membrane origin [8]. Whenof the theybacteria, were its extracted rupture fromand bacterial bacteria orcell fungi, death they [7,9,51,52]. belong toMajor the nonribosomal issues against synthetized AMPs applications peptides have (NRAMP) been class.related When to AMPs’ extracted toxicity from to eukaryotic eukaryotic cells, cells, they poor belong stability to the in ribosomalvivo with synthetizedeventual degra- pep- tidesdation (RAMP) during class.transportation Gramicidin, to their vancomycin target cells and and polymyxin organs [32,51,53,54]. B are examples of NRAMPs, whileAMPs nisin have and melittinbeen classified are RAMPs according [8,55]. to AMPs their usuallyorigin [8]. have When one they or more were secondary extracted structuresfrom bacteria such or as fungi,α−helix, theyβ belong−sheet, toαβ th,e and nonribosomal non−αβ [56 synthetized]. A huge structural peptides diversity (NRAMP) of AMPsclass. When have theextracted common from feature eukaryotic of positive cells, charge they andbelong amphipathic to the ribosomal nature [57 synthetized]. Figure2 illustratespeptides (RAMP) AMPs structures. class. Gramicidin, In Figure2 a,vancomycin gramicidin Aand incorporated polymyxin in bilayerB are examples membranes of canNRAMPs, be seen while as a peptidenisin and dimer melittin traversing are RAMPs the bilayer [8,55]. with AMPs four usually tryptophan have sideone −orchains more assecondary anchors atstructures the membrane such as interface. α−helix, Figureβ−sheet,2b showsαβ, and the non structure−αβ [56]. of A the huge antimicrobial structural frogdiversity skin of peptide AMPs magainin have the ascommon determined feature by of nuclear positive magnetic charge and resonance amphipathic (NMR) nature spectroscopy[57]. Figure in the2 illustrates presence ofAMPs sodium structures. dodecyl In sulfate Figure (SDS) 2a, gramicidin micelles with A incorporated the side−chains in bi- of layer membranes can be seen as a peptide dimer traversing the bilayer with four tryp- Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 28 Int. J. Mol. Sci. 2021, 22, 5424 tophan side−chains as anchors at the membrane interface. Figure 2b shows the structure3 of 27 of the antimicrobial frog skin peptide magainin as determined by nuclear magnetic resonance (NMR) spectroscopy in the presence of sodium dodecyl sulfate (SDS) micelles with the side−chains of lysine and phenylalanine residues [57]. Figure 2c shows LL−37 lysinepeptide and adopting phenylalanine a typical residues α−helical [57]. (orange) Figure2c conformation shows LL −37 in peptide the presence adopting of amicelles. typical αFigure−helical 2d (orange) shows indolicidin conformation in inan the extended presence conformation. of micelles. Figure Figure2d shows2e shows indolicidin the spi- inder an−derived

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