Antimicrobial Macromolecules Research Articles

Effects of Secondary Amine and Molecular Weight on the Biological Activities of Cationic Amphipathic Antimicrobial Macromolecules.

Cationic amphipathic antimicrobial agents inspired by antimicrobial peptides (AMPs) have shown potential in combating multidrug-resistant bacteria because of minimal resistance development. Here, this study focuses on the development of novel cationic amphipathic macromolecules in the form of dendrons and polymers with different molecular weights that employ secondary amine piperidine derivative as the cationic moiety. Generally, secondary amine compounds, especially at low molecular weights, have stronger bacteriostatic, bactericidal, and inner membrane disruption abilities than those of their primary amine counterparts. Low molecular weight D2 dendrons with two cationic centers and one hydrophobic dodecyl chain produce outstanding synergistic activity with the antibiotic rifampicin against Escherichia coli, where one-eighth of the standalone dose of D2 dendrons could reduce the concentration of rifampicin required by up to 4000-fold. The low molecular weight compounds are also less toxic and therefore have higher therapeutic index values compared to compounds with larger molecular weights. This study thus reveals key information that may inform the design of future synthetic AMPs and mimics, specifically, the design of low-molecular-weight compounds with secondary amine as the cationic center to achieve high antimicrobial potency and biocompatibility.

Two plus One: Combination Therapy Tri-systems Involving Two Membrane-Disrupting Antimicrobial Macromolecules and Antibiotics.

The escalating issue of multidrug-resistant (MDR) bacteria indicates the urgent need for new and effective strategies to combat this global health challenge. Here, we describe a new combinatorial approach that can be put forward for experimental therapy application against MDR bacteria. Specifically, we have developed a tri-system that includes the coadministration of two different membrane-disrupting-type antimicrobial agents─a synthetic antimicrobial polymer P and an antimicrobial peptide (AMP) colistin methanesulfonate (Col)─in conjunction with an antibiotic [doxycycline (Dox), rifampicin (Rif), or azithromycin (Azi)]. Traditionally, the administration of membrane-disrupting antimicrobial agents causes toxicity, but, in comparison, we demonstrated synergy and biocompatibility using this combinatorial approach. Checkerboard assays showed the occurrence of synergistic interactions in Col-Dox-P, Col-Rif-P, and Col-Azi-P tri-systems against wild-type and MDR Pseudomonas aeruginosa, with the Col-Dox-P system being the most effective. The ability to synergize thus enables the use of a lower dosage in combinations compared to the standalone agents. The tri-systems not only demonstrated bacteriostatic activity but were also bactericidal. For example, the Col-Dox-P system (at 8, 4, and 8 μg mL-1, respectively) and the Col-Rif-P system (at 4, 8, and 16 μg mL-1, respectively) were able to kill >99.999% of planktonic P. aeruginosa cells within 3 h of treatment. More importantly, an improvement of the therapeutic/selectivity index was achieved via combination therapy. Taking the Col-Dox-P system as an example, its biocompatibility with murine embryonic fibroblast cells was found to be comparable to that of polymer P alone despite the synergistic enhancement in antimicrobial activity of the combination. This resulted in a significant increase in selectivity by 16-fold for the Col-Dox-P combination system compared to P alone. Furthermore, the broad applicability of this tri-system strategy was demonstrated via the successful application of the AMP melittin in place of Col or P. Overall, this study sheds new insights on the application of membrane-disrupting antimicrobial agents in combination therapy and their potential for safer clinical use. Additionally, the information gathered in this study could inform the development of future combination therapy systems involving the simultaneous employment of multiple AMPs with antibiotics.

Facial amphiphilicity index correlating chemical structures with antimicrobial efficacy.

Facial amphiphilicity is an extraordinary chemical structure feature of a variety of antimicrobial peptides and polymers. Vast efforts have been dedicated to small molecular, macromolecular and dendrimer-like systems to mimic this highly preferred structure or conformation, including local facial amphiphilicity and global amphiphilicity. This work conceptualizes Facial Amphiphilicity Index (FAI) as a numerical value to quantitatively characterize the measure of chemical compositions and structural features in dictating antimicrobial efficacy. FAI is a ratio of numbers of charges to rings, representing both compositions of hydrophilicity and hydrophobicity. Cationic derivatives of multicyclic compounds were evaluated as model systems for testing antimicrobial selectivity against Gram-negative and Gram-positive bacteria. Both monocyclic and bicyclic compounds are non-antimicrobial regardless of FAIs. Antimicrobial efficacy was observed with systems having larger cross-sectional areas including tricyclic abietic acid and tetracyclic bile acid. While low and high FAIs respectively lead to higher and lower antimicrobial efficacy, in consideration of cytotoxicity, the sweet spot is typically suited with intermediate FAIs for each specific system. This can be well explained by the synergistic hydrophobic-hydrophobic and electrostatic interactions with bacterial cell membranes and the difference between bacterial and mammalian cell membranes. The adoption of FAI would pave a new avenue toward the design of next-generation antimicrobial macromolecules and peptides.

Surface antimicrobial functionalization with polymers: fabrication, mechanisms and applications.

Undesirable adhesion of microbes such as bacteria, fungi and viruses onto surfaces affects many industries such as marine, food, textile, and healthcare. In particular in healthcare and food packaging, the effects of unwanted microbial contamination can be life-threatening. With the current global COVID-19 pandemic, interest in the development of surfaces with superior anti-viral and anti-bacterial activities has multiplied. Polymers carrying anti-microbial properties are extensively used to functionalize material surfaces to inactivate infection-causing and biocide-resistant microbes including COVID-19. This review aims to introduce the fabrication of polymer-based antimicrobial surfaces through physical and chemical modifications, followed by the discussion of the inactivation mechanisms of conventional biocidal agents and new-generation antimicrobial macromolecules in polymer-modified antimicrobial surfaces. The advanced applications of polymer-based antimicrobial surfaces on personal protective equipment against COVID-19, food packaging materials, biomedical devices, marine vessels and textiles are also summarized to express the research trend in academia and industry.

Optical and Biological Properties of Metal-Containing Macromolecules

Organometallic macromolecular polymers and dendrimers constructed with various chromophores and antimicrobial species are attracting considerable attention. Interest in these materials stems from their exceptional properties and potential applications in the industry as biomedical and photoactive agents, as well as their use as sensors. Over the past few decades, the exponential growth of many new classes of metallo-macromolecules that address these issues has been illustrated. Metal-based antimicrobial macromolecules are rising due to the combination of the multiple interactions of the unique properties of metallic moieties and the effect of the bioactive species. Progress in the field of organometallic photoactive materials derives from their broad applications, including photonic switches and upconversion lasers, in addition to sensors and electronic devices. The aim of this inclusive review is to highlight the design and properties of several types of bioactive and drug delivery macromolecules containing metallic moieties as well as metallopolymers and dendrimers containing organic light-emitting diodes.

Antimicrobial resistance challenged with metal-based antimicrobial macromolecules.

Antimicrobial resistance threatens the achievements of science and medicine, as it deactivates conventional antimicrobial therapeutics. Scientists respond to the threat by developing new antimicrobial platforms to prevent and treat infections from these resistant strains. Metal-based antimicrobial macromolecules are emerging as an alternative to conventional platforms because they combine multiple mechanisms of action into one platform due to the distinctive properties of metals. For example, metals interact with intracellular proteins and enzymes, and catalyse various intracellular processes. The macromolecular architecture offers a means to enhance antimicrobial activity since several antimicrobial moieties can be conjugated to the scaffold. Further, these macromolecules can be fabricated into antimicrobial materials for contact-killing medical implants, fabrics, and devices. As volatilization or leaching out of the antimicrobial moieties from the macromolecular scaffold is reduced, these medical implants, fabrics, and devices can retain their antimicrobial activity over an extended period. Recent advances demonstrate the potential of metal-based antimicrobial macromolecules as effective platforms that prevent and treat infections from resistant strains. In this review these advances are thoroughly discussed within the context of examples of metal-based antimicrobial macromolecules, their mechanisms of action and biocompatibility.

Conjugation of Polyphosphoester and Antimicrobial Peptide for Enhanced Bactericidal Activity and Biocompatibility.

Enhancing the bactericidal activity and moderating the toxicity are two important challenges in the design of upcoming antimicrobial compounds. Herein, antimicrobial macromolecules were developed by conjugating CysHHC10 peptide and polyphosphoester for the modulation of microbiocidal activity and biocompatibility. The conjugation was carried out via thiol-yne "click" chemistry between the cysteine terminal of the peptide and the pendant propargyl moieties of the polyphosphoester. The bactericidal efficacy of the polyphosphoester-peptide conjugates were investigated by microbial growth inhibition toward the Gram-positive and Gram-negative bacteria. On the basis of peptide mass fraction, the polyphosphoester-peptide conjugates exhibited lower values of minimum inhibitory concentration than that of the free peptide. The polyphosphoester-peptide conjugates also exhibited ultralow hemolytic characteristic at a concentration of 4000 μg/mL, indicating significant improvement of erythrocytes compatibility as compared to the free peptide that readily caused lysis of 50% of red blood cells at 1000 μg/mL. Cytotoxicity of the polyphosphoester-peptide conjugates toward 3T3 fibroblast cells was also reduced in comparison to that of the free peptide. Conjugation of the polyphosphoester thus improves the bactericidal efficacy and biocompatibility of the antimicrobial peptide.

Incorporation of Antimicrobial Macromolecules in Acrylic Denture Base Resins: A Research Composition and Update

Contemporary research in acrylic denture base materials focuses on the development of a novel poly(methyl methacrylate) (PMMA) resin with antimicrobial properties. Although PMMA resin has fulfilled all the requirements of an ideal denture base material, its susceptibility to microbial colonization in the oral environment is a formidable concern to clinicians. Many mechanisms including the absence of ionic charge in the methyl methacrylate resins, hydrophobic interactions, electrostatic interactions, and mechanical attachment have been found to contribute to the formation of biofilm. The present article outlines the basic categories of potential antimicrobial polymer (polymeric biocides) formulations (modified PMMA resins) and considers their applicability, biological status, and usage potential over the coming years.

In vitro anti-bacterial and anti-fungal activities of hydrophilic plant defence compounds obtained from the leaves of bell pepper (Capsicum annuum L.)

SummaryHydrophilic extracts from plants contain anti-microbial macromolecules that may be considered when developing natural compounds to control plant pathogens, including anti-microbial peptides that differ structurally from commercial pesticides. This study evaluated the anti-microbial activities of aqueous peptide-enriched fractions from the leaves of bell pepper (Capsicum annuum L. ‘Magali R’) against phytopathogens for biotechnological applications. Fully-expanded bell pepper leaves were frozen, powdered and extracted. The supernatant was labelled the soluble extract (SE), and the precipitate was extracted with LiCl to produce a cell wall extract (CWE). The SE and CWE were then fractionated using ammonium sulphate following molecular exclusion chromatography. Electrophoresis showed that the CWE was a less complex extract. A peptide-enriched fraction (PF) from the CWE was then fractionated by hydrophobic chromatography. Two of the fractions recovered inhibited the growth of Ralstonia solanacearum and Clavibacter michiganensis ssp. michiganensis in vitro. For commercial-scale applications, ultrafiltration (1.0 – 10.0 kDa cut-off) replaced chromatography, for lower cost. The peptide sub-fraction CWE1-10kDa partially controlled the in vitro growth of R. solanacearum, C. michiganensis ssp. michiganensis, and Alternaria solani and showed high activity against Erwinia carotovora ssp. carotovora, with total inhibition at a low concentration of 96.7 mg peptide fruction l–1. CWE1-10kDa represents an aqueous anti-microbial extract that may complement the use of pesticides, and have lower environmental toxicity.

ChemInform Abstract: Antimicrobial Macromolecules: Synthesis, Methods and Future Applications

AbstractReview: 201 refs.

Antimicrobial macromolecules: synthesis methods and future applications

This review article presents important and recent progress in the manufacture and application of antimicrobial macromolecules. Microbial infections continue to endanger human health and pose a great economic burden to society. To resolve this crisis, huge efforts to improve or develop macromolecules that can inhibit pathogens without incurring pathogen resistance are required and actively ongoing. Synthetic antimicrobial macromolecules which include antimicrobial peptides (AMPs), polymers and peptide–polymer hybrids represent a huge class of molecules which can incur effective antimicrobial therapy due to their unique biochemical properties. The use of these antimicrobial macromolecules which target the cytoplasmic membrane of microbes, is a promising approach to lower the propensity of pathogen resistance development. Therefore, huge efforts to synthesize these molecules at scales and purities that enable their structure-function and clinical studies are actively underway. Due to the high cost involved in extracting AMPs from natural sources, biological processes are being developed to economically manufacture AMPs at large scale. Synthetic AMP analogs are also being engineered to further improve antimicrobial potency and lower synthesis cost. Synthetic polymers have also been found to exhibit excellent antimicrobial properties which are comparable to those of natural AMPs. Various antimicrobial polymers have been synthesized based on the amphiphilicity of natural AMPs. Although the facile synthesis of polymers poses no cost problems, numerous synthetic antimicrobial polymers are disadvantaged by high toxicity to mammalian cells due to their non-selectivity. To combine the advantages of AMPs and antimicrobial polymers, peptide-polymer hybrid macromolecules are actively being developed, with a few effective and strongly microbicidal models recently demonstrated. With the advancement of biochemical engineering tools and chemical synthesis methods, these antimicrobial macromolecules can be specifically designed to be highly selective, broad spectrum and biocompatible. In this review, we summarize the recent advances and challenges in the manufacture of these antimicrobial macromolecules. Based on their antimicrobial mechanisms, their applications in addressing challenges associated with infectious disease and antibiotic-resistance are also discussed.