A dual-targeting antifungal is effective against multidrug-resistant human fungal pathogens.

Drug-resistant fungal infections pose a significant threat to human health. Dual-targeting compounds, which have multiple targets on a single pathogen, offer an effective approach to combat drug-resistant pathogens, although ensuring potent activity and high selectivity remains a challenge. Here we propose a dual-targeting strategy for designing antifungal compounds. We incorporate DNA-binding naphthalene groups as the hydrophobic moieties into the host defence peptide-mimicking poly(2-oxazoline)s. This resulted in a compound, (Gly0.8Nap0.2)20, which targets both the fungal membrane and DNA. This compound kills clinical strains of multidrug-resistant fungi including Candida spp., Cryptococcus neoformans, Cryptococcus gattii and Aspergillus fumigatus. (Gly0.8Nap0.2)20 shows superior performance compared with amphotericin B by showing not only potent antifungal activities but also high antifungal selectivity. The compound also does not induce antimicrobial resistance. Moreover, (Gly0.8Nap0.2)20 exhibits promising in vivo therapeutic activities against drug-resistant Candida albicans in mouse models of skin abrasion, corneal infection and systemic infection. This study shows that dual-targeting antifungal compounds may be effective in combating drug-resistant fungal pathogens and mitigating fungal resistance.

Peptide-Mimicking Poly(2-oxazoline)s Possessing Potent Antifungal Activity and BBB Penetrating Property to Treat Invasive Infections and Meningitis.

Invasive fungal infections, including meningitis, cause a high mortality rate due to few available antifungal drugs and frequently associated side effects and quick emergence of drug-resistant fungi. The restrictive permeability of the blood-brain barrier (BBB) further limits the efficacy of antifungal agents substantially in treating meningitis. Hereby, we design and synthesize guanidinium-functionalized poly(2-oxazoline)s by mimicking cell-penetrating peptides. The optimal polymer, PGMeOx10 bearing a methylene spacer arm, displays potent activities against the drug-resistant fungi and biofilm, negligible toxicity, and insusceptibility to antimicrobial resistance. Moreover, PGMeOx10 can break BBB retractions to exert promising antifungal functions in the brain. PGMeOx10 demonstrates potent in vivo antifungal therapeutic efficacy in mouse models including skin infection, systemic infections, and meningitis. PGMeOx10 effectively rescues infected mice and reduces fungal burden and inflammation in the brain. These results and the excellent biosafety of poly(2-oxazoline)s indicate the effectiveness and potential of our strategy to design promising antifungal agents in treating systemic infections and meningitis.

Effect of aggregation behavior on microplastic removal by magnetic Fe3O4 nanoparticles.

Magnetic nanotechnologies have been shown to be an efficient approach to the reduction of microplastic (MP) pollution in aquatic environments. However, uncertainties remain regarding the relationship between particle stability and MP removal under varying water conditions, hindering the practical application of magnetic nanotechnologies for MP removal. Herein, the influence of particle aggregation behavior on nano-scale MP removal by Fe3O4 nanoparticles (FNPs) was investigated, by monitoring dynamic light scattering parameters and analyzing the microstructures of particle aggregates. Results showed that 83.1 %-92.9 % of MPs could be removed by FNPs within 1 h, and MP removal exhibited a high degree of Pearson correlation (R = 0.95; P = 0.04) with particle aggregation behavior mediated by the FNPs dosage. Furthermore, pH-dependent electrostatic interactions significantly influenced particle aggregation behavior and the removal of MPs. Under pH <6.7 conditions, electrostatic attraction between electropositive FNPs and electronegative MPs led to charge neutralization-induced aggregation and efficient removal MP performance. Under increasingly saline conditions, compression of the electrical double layer enhanced the self-aggregation behavior of MPs, weakening the electrostatic repulsion between FNPs and MPs under alkaline conditions. Therefore, salinity improved the MP removal efficiency, especially under alkaline conditions, with MP removal increasing from 4.47 % to 55.1 % when the mass fraction of NaCl was increased from 0 % to 1 %. These findings further our understanding of the effect of aggregation behavior on MP removal by FNPs and highlight the potential for magnetic nanotechnology application in the removal of nano-scale MPs from aquatic environments, while also providing valuable insights for the design of FNP-based materials.

Host-Defense-Peptide-Mimicking ß-Peptide Polymer Acting as a Dual-Modal Antibacterial Agent by Interfering Quorum Sensing and Killing Individual Bacteria Simultaneously.

Host defense peptides (HDPs) are one of the potentially promising agents for infection diseases due to their broad spectrum and low resistance rate, but their clinical applications are limited by proteolytic instability, high-cost, and complicated synthesis process. Here, we report a host-defense-peptide-mimicking ß-peptide polymer that resists proteolysis to have enhanced the activity under physiological conditions, excellent antimicrobial efficiency even at high density of bacteria, and low cost for preparation. The ß-peptide polymer demonstrated quorum sensing (QS) interference and bactericidal effect against both bacterial communities and individual bacterium to simultaneously block bacterial communication and disrupt bacterial membranes. The hierarchical QS network was suppressed, and main QS signaling systems showed considerably down-regulated gene expression, resulting in excellent biofilm eradication and virulence reduction effects. The dual-modal antibacterial ability possessed excellent therapeutic effects in Pseudomonas aeruginosa pneumonia, which could inhibit biofilm formation and exhibit better antibacterial and anti-inflammatory efficiency than clinically used antibiotics, levofloxacin. Furthermore, the ß-peptide polymer also showed excellent therapeutic effect Escherichia coli pyogenic liver abscess. Together, we believed that the ß-peptide polymer had a feasible clinical potential to treat bacterial infection diseases.

Advance and Designing Strategies in Polymeric Antifungal Agents Inspired by Membrane-Active Peptides.

The high-mortality invasive fungal infections seriously threaten the lives of immunocompromised people. Host defense peptides and cell-penetrating peptides are representative membrane-active peptides with different functions. Among them, host defense peptides mimicking is a valid strategy in the design of synthetic antifungal agents. Despite the brilliance in the field of intracellular delivery, the potential of cell-penetrating peptides and their mimics for designing antifungal agents has been overlooked. In this concept article, we describe the structural design of synthetic antifungal polymers as mimics of host defense peptides, and highlight the effectiveness and potential of cell-penetrating peptide-inspired strategy in designing potent and selective antifungal polymeric agents. In addition, an outlook for further expanding the design horizons of antifungal polymers is also presented.

Biodegradable peptide polymers as alternatives to antibiotics used in aquaculture.

The pressure of antimicrobial resistance has forced many countries to reduce or even prohibit the use of antibiotics in feed. Therefore, it is an urgent need to develop alternatives to antibiotics to control infectious diseases in feed and aquaculture. To address this long-lasting challenge, we prepared peptide polymers that display potent and broad-spectrum activity against common pathogenic bacteria in aquaculture, low hemolysis and low cytotoxicity, and do not induce bacteria to develop resistance or cross-resistance to antibiotics. The optimal peptide polymer demonstrates strong in vivo therapeutic potential in an adult zebrafish infection model. Moreover, the optimal peptide polymer is biodegradable by enzymes into single amino acids and dipeptides to totally lose its antibacterial activity and, therefore, will not cause antimicrobial selective pressure. Our study suggests that peptide polymers are promising alternatives to antibiotics in aquaculture and open new avenues to address the global challenge of antimicrobial resistance.

An Effective Strategy to Develop Potent and Selective Antifungal Agents from Cell Penetrating Peptides in Tackling Drug-Resistant Invasive Fungal Infections.

The high mortality rate of invasive fungal infections and quick emergence of drug-resistant fungal pathogens urgently call for potent antifungal agents. Inspired by the cell penetrating peptide (CPP) octaarginine (R8), we elongated to 28 residues poly(d,l-homoarginine) to obtain potent toxicity against both fungi and mammalian cells. Further incorporation of glutamic acid residues shields positive charge density and introduces partial zwitterions in the obtained optimal peptide polymer that displays potent antifungal activity against drug-resistant fungi superior to antifungal drugs, excellent stability upon heating and UV exposure, negligible in vitro and in vivo toxicity, and strong therapeutic effects in treating invasive fungal infections. Moreover, the peptide polymer is insusceptible to antifungal resistance owing to the unique CPP-related antifungal mechanism of fungal membrane penetration followed by disruption of organelles within fungal cells. All these merits imply the effectiveness of our strategy to develop promising antifungal agents.

Microbial Metabolite Inspired ß-Peptide Polymers Displaying Potent and Selective Antifungal Activity.

Potent and selective antifungal agents are urgently needed due to the quick increase of serious invasive fungal infections and the limited antifungal drugs available. Microbial metabolites have been a rich source of antimicrobial agents and have inspired the authors to design and obtain potent and selective antifungal agents, poly(DL-diaminopropionic acid) (PDAP) from the ring-opening polymerization of ß-amino acid N-thiocarboxyanhydrides, by mimicking ε-poly-lysine. PDAP kills fungal cells by penetrating the fungal cytoplasm, generating reactive oxygen, and inducing fungal apoptosis. The optimal PDAP displays potent antifungal activity with minimum inhibitory concentration as low as 0.4 µg mL-1 against Candida albicans, negligible hemolysis and cytotoxicity, and no susceptibility to antifungal resistance. In addition, PDAP effectively inhibits the formation of fungal biofilms and eradicates the mature biofilms. In vivo studies show that PDAP is safe and effective in treating fungal keratitis, which suggests PDAPs as promising new antifungal agents.

Short Guanidinium-Functionalized Poly(2-oxazoline)s Displaying Potent Therapeutic Efficacy on Drug-Resistant Fungal Infections.

New antifungals are urgently needed to combat invasive fungal infections, due to limited types of available antifungal drugs and frequently encountered side effects, as well as the quick emergence of drug-resistance. We previously developed amine-pendent poly(2-oxazoline)s (POXs) as synthetic mimics of host defense peptides (HDPs) to have antibacterial properties, but with poor antifungal activity. Hereby, we report the finding of short guanidinium-pendent POXs, inspired by cell-penetrating peptides, as synthetic mimics of HDPs to display potent antifungal activity, superior mammalian cells versus fungi selectivity, and strong therapeutic efficacy in treating local and systemic fungal infections. Moreover, the unique antifungal mechanism of fungal cell membrane penetration and organelle disruption explains the insusceptibility of POXs to antifungal resistance. The easy synthesis and structural diversity of POXs imply their potential as a class of promising antifungal agents.

A sandcastle worm-inspired strategy to functionalize wet hydrogels.

Hydrogels have been extensively used in many fields. Current synthesis of functional hydrogels requires incorporation of functional molecules either before or during gelation via the pre-organized reactive site along the polymer chains within hydrogels, which is tedious for polymer synthesis and not flexible for different types of hydrogels. Inspired by sandcastle worm, we develop a simple one-step strategy to functionalize wet hydrogels using molecules bearing an adhesive dibutylamine-DOPA-lysine-DOPA tripeptide. This tripeptide can be easily modified with various functional groups to initiate diverse types of polymerizations and provide functional polymers with a terminal adhesive tripeptide. Such functional molecules enable direct modification of wet hydrogels to acquire biological functions such as antimicrobial, cell adhesion and wound repair. The strategy has a tunable functionalization degree and a stable attachment of functional molecules, which provides a tool for direct and convenient modification of wet hydrogels to provide them with diverse functions and applications.

Addressing MRSA infection and antibacterial resistance with peptoid polymers.

Methicillin-Resistant Staphylococcus aureus (MRSA) induced infection calls for antibacterial agents that are not prone to antimicrobial resistance. We prepare protease-resistant peptoid polymers with variable C-terminal functional groups using a ring-opening polymerization of N-substituted N-carboxyanhydrides (NNCA), which can provide peptoid polymers easily from the one-pot synthesis. We study the optimal polymer that displays effective activity against MRSA planktonic and persister cells, effective eradication of highly antibiotic-resistant MRSA biofilms, and potent anti-infectious performance in vivo using the wound infection model, the mouse keratitis model, and the mouse peritonitis model. Peptoid polymers show insusceptibility to antimicrobial resistance, which is a prominent merit of these antimicrobial agents. The low cost, convenient synthesis and structure diversity of peptoid polymers, the superior antimicrobial performance and therapeutic potential in treating MRSA infection altogether imply great potential of peptoid polymers as promising antibacterial agents in treating MRSA infection and alleviating antibiotic resistance.

Peptide-Mimicking Poly(2-oxazoline)s Displaying Potent Antimicrobial Properties.

Poly(2-oxazoline)s have excellent biocompatibility and have been used as FDA-approved indirect food additives. The inert property of the hydrophilic poly(2-oxazoline)s suggests them as promising substitutes for poly(ethylene glycol) (PEG) in various applications such as anti-biofouling agents. It was recently reported that poly(2-oxazoline)s themselves have antimicrobial properties as synthetic mimics of host defense peptides. These studies revealed the bioactive properties of poly(2-oxazoline)s as a new class of functional peptide mimics, by mimicking host defense peptides to display potent and selective antimicrobial activities against methicillin-resistant Staphylococcus aureus both in vitro and in vivo, without concerns about antimicrobial resistance. The high structural diversity, facile synthesis, and potent and tunable antimicrobial properties underscore the great potential of poly(2-oxazoline)s as a class of novel antimicrobial agents in dealing with drug-resistant microbial infections and antimicrobial resistance.

An alpha/beta chimeric peptide molecular brush for eradicating MRSA biofilms and persister cells to mitigate antimicrobial resistance.

Infections involving methicillin-resistant Staphylococcus aureus present great challenges, especially when biofilms and persister cells are involved. In this work, an α/ß chimeric polypeptide molecular brush (α/ß CPMB) is reported to show excellent performance in inhibiting the formation of biofilms and eradicating established biofilms. Additionally, the polymer brush efficiently killed metabolically inactive persister cells that are antibiotic-insensitive. Antimicrobial mechanism studies showed that α/ß CPMB causes membrane disturbance and a substantial increase in reactive oxygen species (ROS) levels to kill bacteria, and mesosome-like structure formation was also observed. Furthermore, the polymer brush was able to kill clinically isolated multidrug resistant Gram-positive bacteria with no risk of antimicrobial resistance. The α/ß CPMB has demonstrated great potential in addressing the great challenge of eradicating multidrug resistant Gram-positive bacterial infections.

Poly(2-Oxazoline)-Based Functional Peptide Mimics: Eradicating MRSA Infections and Persisters while Alleviating Antimicrobial Resistance.

Peptides have important biological functions. However, their susceptibility to proteolysis limits their applications. We demonstrated here for the first time, that poly(2-oxazoline) (POX) can work as a functional mimic of peptides. POX-based glycine pseudopeptides, a host defense peptide mimic, had potent activities against methicillin-resistant S. aureus, which causes formidable infections. The POX mimic showed potent activity against persisters that are highly resistant to antibiotics. S. aureus did not develop resistance to POX owning to the reactive oxygen species related antimicrobial mechanism. POX-treated S. aureus is sensitive to common antibiotics, demonstrating no observable antimicrobial pressure or cross-resistance in using antimicrobial POX. This study highlights POX as a new type of functional mimic of peptides and opens new avenues in designing and exploring peptide mimetics for biological functions and applications.

Host Defense Peptide Mimicking Peptide Polymer Exerting Fast, Broad Spectrum, and Potent Activities toward Clinically Isolated Multidrug-Resistant Bacteria.

Multidrug-resistant (MDR) bacteria have emerged quickly and have caused serious nosocomial infections. It is urgent to develop novel antimicrobial agents for treating MDR bacterial infections. In this study, we isolated 45 strains of bacteria from hospital patients and found shockingly that most of these strains were MDR to antimicrobial drugs. This inspired us to explore antimicrobial peptide polymers as synthetic mimics of host defense peptides in combating drug-resistant bacteria and the formidable antimicrobial challenge. We found that peptide polymer 80:20 DM:Bu (where DM is a hydrophilic/cationic subunit and Bu is a hydrophobic subunit) displayed fast bacterial killing, broad spectrum, and potent activity against clinically isolated strains of MDR bacteria. Moreover, peptide polymer 80:20 DM:Bu displayed potent in vivo antibacterial efficacy, comparable to the performance of polymyxin B, in a Pseudomonas aeruginosa (P. aeruginosa) infected rat full-thickness wound model. The peptide polymer can be easily synthesized from ring-opening polymerization with remarkable reproducibility in structural properties and biological activities. The peptide polymer's potent and broad spectrum antimicrobial activities against MDR bacteria in vitro and in vivo, resistance to proteolysis, and high structural diversity altogether imply a great potential of peptide polymer 80:20 DM:Bu in antimicrobial applications as synthetic mimics of host defense peptides.

Peptide polymer displaying potent activity against clinically isolated multidrug resistant Pseudomonas aeruginosa in vitro and in vivo.

Multidrug resistant (MDR) Pseudomonas aeruginosa has caused serious nosocomial infections owing to its high intrinsic resistance and ease of acquiring resistance to common antibiotics. There is an urgent need to develop antimicrobial agents against MDR Pseudomonas aeruginosa. Here we report a 27-mer peptide polymer 90 : 10 DLL : BLG, as a synthetic mimic of a host defense peptide, that displayed potent in vitro and in vivo activities against multiple strains of clinically isolated MDR Pseudomonas aeruginosa, performing even better than antibiotics within our study. This peptide polymer also showed negligible hemolysis and low cytotoxicity, as well as quick bacterial killing efficacy. The structural diversity of peptide polymers, their easy synthesis from lithium hexamethyldisilazide-initiated fast N-carboxyanhydride polymerization, and the excellent reproducibility of their chemical structure and biological profiles altogether suggested great potential for antimicrobial applications of peptide polymers as synthetic mimics of host defense peptides.

Removal of hexavalent chromium from water by modified sponge iron particles and insights into mechanism.

Sponge iron particles modified with expanded graphite and Cu were used to purify solutions contaminated with aqueous Cr(VI). A removal mechanism that involved physical adsorption and a redox reaction is proposed. The reaction, which consisted of rapid adsorption, a desorption stage, and an adsorption-desorption equilibrium stage, corresponded to a first-order kinetic model. The properties of the adsorption materials before and after use were investigated by X-ray diffraction, scanning electron microscopy-energy-dispersive spectroscopy, Fourier-transform infrared spectroscopy, energy-dispersive X-ray fluorescence spectroscopy, and surface area measurements. Changes in the surface properties, e.g., attachment of material to the surface and filling of pores with Cr, were clearly observed. The Langmuir model best described Cr(VI) adsorption on the sponge iron and its modified particles. Removal efficiencies of 98.7, 98.8, and 100% were achieved in 7 h at a Cr(VI) dosage of 10 mg/L. Sponge iron particles are therefore potential adsorbents and after modification give good removal of Cr(VI) ions from contaminated water.