Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 + 1989 word(s) 1989 2021-01-13 17:38:22 |
2 format correct Meta information modification 1989 2021-01-19 03:51:58 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Alfei, S. Ammonium Terminated Antibacterial Dendrimers. Encyclopedia. Available online: https://encyclopedia.pub/entry/6432 (accessed on 16 June 2024).
Alfei S. Ammonium Terminated Antibacterial Dendrimers. Encyclopedia. Available at: https://encyclopedia.pub/entry/6432. Accessed June 16, 2024.
Alfei, Silvana. "Ammonium Terminated Antibacterial Dendrimers" Encyclopedia, https://encyclopedia.pub/entry/6432 (accessed June 16, 2024).
Alfei, S. (2021, January 14). Ammonium Terminated Antibacterial Dendrimers. In Encyclopedia. https://encyclopedia.pub/entry/6432
Alfei, Silvana. "Ammonium Terminated Antibacterial Dendrimers." Encyclopedia. Web. 14 January, 2021.
Ammonium Terminated Antibacterial Dendrimers
Edit

Tapping into our review recently published in Nanomaterials and available on line at https://www.mdpi.com/2079-4991/10/10/2022/htm, we have created two entry on Encyclopedia. The first one consists in a general overview concerning antibacterial cationic dendrimers, followed by an updated review about the PAMAM and PPI-based cationic dendrimers developed in the last decade (https://encyclopedia.pub/7167), which showed considerable antibacterial properties. In the second entry, we have provided an updated overview concerning the most studied class of antibacterial cationic dendrimers, i.e. the dendrimeric antimicrobial peptides (https://encyclopedia.pub/7223). This third entry collects the main case studies concerning the antibacterial cationic dendrimers having different internal scaffolds, but peripherally positively charged due to the presence of terminal ammonium groups.

positively charged antibacterial dendrimers ammonium-terminated dendrimers phosphorous dendrimers carbosilane dendrimers ruthenium and zinc encased phtalocyanine dendrimer

1. Introduction

Resistant bacterial strains are responsible of serious infections, in particular in nosocomial settings, impossible to be treated with traditional antibiotics. Furthermore, the particular form of resistance supported by biofilm production, hinder the durability, reliability, and performance of many medical devices and implants. In this regard, the development of new antibacterial agents and antibiofilm strategies, such as antibacterial coatings that repel bacteria and prevent biofilm formation are highly urgent. Natural cationic antimicrobial peptides (CAMPs), which are capable to kill pathogens simply through external contact, without the need to address the numerous resistance mechanisms due to genetic mutations that bacteria can develop, represent a promising option to conventional antibiotics. Unfortunately, high costs of production, instability and low selectivity for bacteria, limit their clinical application. Inspired by natural CAMPs, cationic antimicrobial macromolecules including dendrimers (Ds) have shown to function as antibacterial agents and as antimicrobial surface coatings as well. Different types of dendrimers, including cationic ones, have been developed for the treatment of infections sustained by multidrug-resistant bacteria, mainly during the last decade. Commercially available PAMAM and PPI-based dendrimers, as well as several their dendrimer derivatives which proved to possess in vitro broad-spectrum activities, have been reviewed in a recent entry on Encyclopedia (https://encyclopedia.pub/7167). In a second entry, we have provided an updated overview concerning the most studied class of cationic antibacterial dendrimers (CADs), i.e. the antimicrobial peptide ones. Now, we have herein collected the main case studies concerning the antibacterial cationic dendrimers having different internal scaffolds, but peripherally positively charged due to the presence of terminal ammonium groups.

2. Ammonium-Terminated Dendrimers

As happens among cationic antimicrobial polymers [1], also among CADs a class is represented by dendrimers which, despite having structurally different internal matrices, possess peripheral protonated amino groups, responsible for their cationic character and essential for their antibacterial potency. Second-generation (G2) ammonium-terminated Ds were prepared by synthesizing Boc-protected precursor Ds (G2-Boc), with a divergent synthetic strategy through polymerization of t-butyloxycarbonyl-aminoethyl acrylate (Boc-AEA), followed by deprotection treatment with trifluoroacetic acid (TFA) to remove Boc groups [2]. In plate killing essays, the G2 dendrimer obtained showed high antimicrobial activity against E. coli and S. aureus species (MBC99.9 = 3–8 μg/mL and 4 μg/mL respectively), associated with very low hemolytic toxicity (<10% at concentration of 1024 μg/mL). Interestingly, since net cationic membrane-disruptive antimicrobials may elicit an immune attack when administered intravenously, Xu’s same group, having cloaked a G2 dendrimer with poly(caprolactone-b-ethylene glycol) (PCL-b-PEG), obtained a new antimicrobial, G2-g-(PCL-b-PEG), which exhibits neutral surface charge. The neutral dendrimer was able to kill >99.9% of the inoculated bacterial cells, at ≤8 μg/mL, it exhibited good colloidal stability in the presence of serum and it showed insignificant hemolytic toxicity, even at concentrations ≥2048 μg/mL. The authors attributed the maintained antimicrobial activity of the neutral dendrimer to the degradation of the neutral shell due to bacterial lipase and the consequent exposure of the membrane-disruptive bactericidal cationic G2 core.

Semisynthetic ammonium-terminated gallic acid-triethylene glycol Ds (GATG) developed by Leire et al. (2016) have been shown to be able to interact with bacteria, thus attracting researchers as potential multivalent macromolecules for the development of new antimicrobials[3]. GATG Ds, due to the presence of primary amines in their periphery, were capable of sequestering bacteria cells and to induce the formation of clusters in Vibrio harveyi, an opportunistic marine luminescent pathogen. This property was dependent on dendrimer generations and was more potent than that of poly(N-[3-(dimethylamino)propyl]methacrylamide) [p(DMAPMAm)], a cationic linear polymer previously shown to cluster bacteria. The authors also investigated the bacteria viability within the formed clusters and the quorum sensing activity, responsible for light production in V. harveyi. The results suggested that GATG Ds may activate microbial responses by maintaining a high concentration of quorum sensing signals within the clusters and by increasing permeability of the microbial OM, with the growth of their generation. In particular, when bacteria cells were exposed to third-generation GATG Ds, more than 85% of population had OM damaged. The GATG Ds developed by Leire et al. might constitute a valuable platform for the development of novel antimicrobial materials which can affect microbial viability and/or virulence.

By using the robust copper (I) catalyzed alkyne-azide cycloaddition (CuAAC) “click reaction” for dendrimer synthesis and for post-synthesis functionalization, Ladd et al. reported a versatile divergent methodology to construct ammonium-terminated Ds from the tetrafunctional core pentaerythritol[4]. Ds of generations 0–3 (G0–G3) were achieved with from 4 to 32 acetylene surface groups, which in G0–G2 Ds were subsequently used to covalently link cationic amino groups. The authors explored the bactericidal efficacy of the cationic amine terminated Ds G0-NH3+-G3NH3+ determining MIC and MBC values against the E. coli ATCC 11229TM strain. The results asserted that the bacteriostatic and bactericidal activity of the prepared Ds depended on their size, functional end groups and hydrophilicity, as already established in many studies in the field. In particular, G0 dendrimer displayed poor antibacterial activity, with MIC values in the range 29–59 μM and MBC values > 59 μM, while G2 and G1 Ds displayed from good to strong antibacterial activity. In the authors’ opinion, the octacationic first-generation dendrimer was the most potent antimicrobial dendrimer displaying MIC values (0.9 μg/mL, 0.26 μM) and MBC values (4–8 μg/mL, 1.1–2.3 μM) that were lower than those of several previously studied Ds. In our opinion, and considering when the MIC values are expressed in μM (which takes into account the MW of the Ds and which provides the actual equivalents of Ds able to exert a certain effect), rather than in μg/mL, the G2 dendrimer can be considered the most active antimicrobial device (MIC value = 0.12 μM vs. 0.26 μM). Furthermore, although the Ds developed by Ladd and colleagues may appear very promising, the absence of investigations into their cytotoxicity and hemolytic toxicity prevents them from being considered suitable for clinical applications.

Ammonium-Terminated Phosphorous Dendrimers

By performing a sol-gel process, the fruitful association of a fourth-generation phosphorus dendrimer, peripherally modified with quaternized ethylene diamine and titanium dioxide (TiO2), was realized by Milowska et al. (2015) together with other three ones[5]. The hybrid mesoporous dendrimer-coated TiO2 obtained showed to be nanosized, in a crystalline and to possess a surface mimicking that one of PEI-Ds. It was investigated for its toxicity on red blood cells (RBCs), its cytotoxicity toward B14 Chinese fibroblasts and its antimicrobial activity against some strains of bacteria and yeast. The dendrimer proved appreciable antibacterial activity on S. aureus and S. epidermidis MSSE strains at MIC = 500 μg/mL in both cases. Nevertheless, considering that in hemolytic and cytotoxicity essays it showed a HC50 value of 100 μg/mL and an IC50 of 25 μg/mL, its antimicrobial activity must be considered questionable.

2.1. Ammonium-Terminated Carbosilane Dendrimers

Cationic carbosilane Ds have shown their potential to be used as devices in several biomedical applications including as bactericides[5]. Both silicon containing hyperbranched polymers and Ds are interesting as organic-inorganic hybrid materials, due to the presence of C–Si bonds, that confer high stability and very low hydrophilicity, favorable to the processes of bio permeability[6]. Nevertheless, when preparing cationic materials for antimicrobial uses, hydrophobicity must be tuned by functionalizing the macromolecules with cationic groups, thus achieving good levels of water solubility, a pivotal requirement for antibacterial studies. In this context, among other cationic materials, including hyperbranched polymers, some second- and third-generation (G2 and G3) cationic Ds, based on a carbosilane scaffold, but peripherally decorated with ammonium groups, were prepared by Ortega et al. (2011) and proposed as antibacterial agents. Although slightly less active that the hyperbranched analogous, the cationic carbosilane Ds exhibited considerable antimicrobial activities against the Gram-negative E. coli and against the Gram-positive S. aureus, with MIC values in the range of 16–64 μg/mL and 4–8 μg/mL, respectively. MBC values, also calculated against the same strains, were in the ranges of 32–54 μg/mL and 8 μg/mL, respectively. The materials studied by Ortega and colleagues seem very promising as novel broad-spectrum antimicrobial agents, but, since research on their cytotoxicity, hemolytic toxicity, and selectivity is missing, their suitability for clinical uses cannot be taken for granted.

Recently, Fernandez and colleagues (2019) synthetized G1 and G2 carbosilane dendrons and, using a selection of three different CAMPs, created a series of nanocomposites either by covalent links or by physical non-covalent interactions, with the aim of establishing synergistic or collaborative relations between both types of molecules[7]. The authors speculated that the carbosilane dendrimer structures, already known for their on contact antibacterial potency against Gram-positive and Gram-negative bacteria strains and for their poor tendency to induce resistances probably due to their easier penetration into the phospholipid bilayer could help to protect or transport AMPs inside bacterial membranes. The antibacterial activity of ammonium-terminated carbosilane Ds (namely 3 and 4) was assessed against E. coli and S. aureus strains and was compared to that of the four nanocomposites [namely 11, 14 (covalent nanoconjugates) and 15, 16 (non-covalent nanoconjugates)] obtained. The MIC values calculated for both groups of compounds were comparable in the case of E. coli, but not in the case of S. aureus, since the nanocomposites (11, 15) displayed a significantly higher antibacterial activity than that of corresponding dendrons (3) (MIC values of 32 and 64 μg/mL vs. 128 μg/mL, respectively). This trend also applied to the nanocomposite (16), when compared to the corresponding dendron (4) (MIC value of 4 μg/mL vs. 8 μg/mL).

2.2. Ammonium-Terminated Ruthenium and Zinc Encased Phtalocyanines (Pcs) Dendrimers

An appealing approach to fight superficial and localized infectious diseases caused by MDR bacteria includes the antimicrobial photodynamic therapy (aPDT), which consists of an adequate combination of three factors: light, oxygen and a light-active compound defined photosensitizer (PS). Their combination leads to the formation of highly reactive oxygen species (ROS), responsible for the cytotoxic damage. Since Pc derivatives including metal core atoms such as zinc, ruthenium, or silicon have photosensitizing activity, they hold promise for various biomedical applications, including cancer therapy. However, due to their highly hydrophobic nature, Pcs require appropriate functionalization or combination with delivery systems to allow adequate administration. In this regard, to obtain photosensitizers macromolecules capable of photoinactivation performance against representative microorganisms, the Gonzalez group (2017) synthetized two families of ammonium-terminated phthalocyanine Ds[8]. Four different categories of photosensitizer cationic Ds, made of zinc and ruthenium Pcs encased in multi-cationic Ds (namely ZnPc, ZnPc1, RuPc and ZnPc1) were essayed against S. aureusE. coli and Candida albicans strains, upon red light irradiation, to assess their potential use as broad-spectrum photo-inactivating agents. All the Pcs Ds were more active against S. aureus than against E. coli, and zinc-coordinated Pcs were more active than ruthenium Pcs against both bacteria species. Octacationic ZnPc1 was slightly more powerful than tetracationic ZnPc against S. aureus, while the contrary was observed against E. coli. Vice versa, tetracationic RuPc was more active than octacationic RuPc1 against S. aureus, since RuPc1 was practically ineffective against E. coli. In fact, it caused a minimal reduction of the colony forming units per milliliter (CFU/mL), at the maximum tested concentration of 10 μM in the presence of the higher light-doses of 60 J cm−2. In particular, when tested against S. aureus, the most active compounds ZnPc1 and ZnPc produced over 6-log10 CFU/mL reductions at 1 μM in the presence of the higher light-doses and a bactericidal effect (3-log10 CFU/mL reduction) when irradiating at 60 J cm−2 with a concentration of 0.6 μM. When essayed against E. coli, reductions over 6-log10 CFU/mL were achieved at concentrations as low as 2.5 μM for ZnPc and 5 μM for ZnPc1 at 30 J cm−2 light dose.

References

  1. Alfei, S.; Schito, A.M. Positively Charged Polymers as Promising Devices against Multidrug Resistant Gram-Negative Bacteria: A Review. Polymers 2020, 12, 1195.
  2. Xu, L.; He, C.; Hui, L.; Xie, Y.; Li, J.-M.; He, W.-D.; Yang, L. Bactericidal Dendritic Polycation Cloaked with Stealth Material via Lipase-Sensitive Intersegment Acquires Neutral Surface Charge without Losing Membrane-Disruptive Activity. ACS Appl. Mater. Interfaces 2015, 7, 27602–27607.
  3. Leire, E.; Amaral, S.P.; Louzao, I.; Winzer, K.; Alexander, C.; Fernandez-Megia, E.; Fernandez-Trillo, F. Dendrimer mediated clustering of bacteria: Improved aggregation and evaluation of bacterial response and viability. Biomater. Sci. 2016, 4, 998–1006.
  4. Ladd, E.; Sheikhi, A.; Li, N.; Van de Ven, T.G.; Kakkar, A. Design and Synthesis of Dendrimers with Facile Surface Group Functionalization, and an Evaluation of Their Bactericidal Efficacy. Molecules 2017, 22, 868.
  5. Milowska, K.; Rybczyńska, A.; Mosiolek, J.; Durdyn, J.; Szewczyk, E.M.; Katir, N.; Brahmi, Y.; Majoral, J.-P.; Bousmina, M.; Bryszewska, M.; et al. Biological Activity of Mesoporous Dendrimer-Coated Titanium Dioxide: Insight on the Role of the Surface–Interface Composition and the Framework Crystallinity. ACS Appl. Mater. Interfaces 2015, 7, 19994–20003.
  6. Ortega, P.; Cobaleda, B.M.; Hernández-Ros, J.M.; Fuentes-Paniagua, E.; Sánchez-Nieves, J.; Tarazona, M.P.; Copa-Patiño, J.; Soliveri, J.; de la Mata, F.J.; Gómez, R. Hyperbranched polymers versus dendrimers containing a carbosilane framework and terminal ammonium groups as antimicrobial agents. Org. Biomol. Chem. 2011, 9, 5238–5248.
  7. Fernandez, J.; Acosta, G.; Pulido, D.; Malý, M.; Copa-Patiño, J.L.; Soliveri, J.; Royo, M.; Gómez, R.; Albericio, F.; Ortega, P.; et al. Carbosilane Dendron–Peptide Nanoconjugates as Antimicrobial Agents. Mol. Pharm. 2019, 16, 2661–2674.
  8. Ruiz-González, R.; Setaro, F.; Gulías, Ò.; Agut, M.; Hahn, U.; Torres, T.; Nonell, S. Cationic phthalocyanine dendrimers as potential antimicrobial photosensitisers. Org. Biomol. Chem. 2017, 15, 9008–9017.
More
Information
Subjects: Microbiology
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
View Times: 386
Revisions: 2 times (View History)
Update Date: 19 Jan 2021
1000/1000
Video Production Service