Showing papers by "Yi Yan Yang published in 2021"

Accelerated antimicrobial discovery via deep generative models and molecular dynamics simulations.

Abstract: The de novo design of antimicrobial therapeutics involves the exploration of a vast chemical repertoire to find compounds with broad-spectrum potency and low toxicity. Here, we report an efficient computational method for the generation of antimicrobials with desired attributes. The method leverages guidance from classifiers trained on an informative latent space of molecules modelled using a deep generative autoencoder, and screens the generated molecules using deep-learning classifiers as well as physicochemical features derived from high-throughput molecular dynamics simulations. Within 48 days, we identified, synthesized and experimentally tested 20 candidate antimicrobial peptides, of which two displayed high potency against diverse Gram-positive and Gram-negative pathogens (including multidrug-resistant Klebsiella pneumoniae) and a low propensity to induce drug resistance in Escherichia coli. Both peptides have low toxicity, as validated in vitro and in mice. We also show using live-cell confocal imaging that the bactericidal mode of action of the peptides involves the formation of membrane pores. The combination of deep learning and molecular dynamics may accelerate the discovery of potent and selective broad-spectrum antimicrobials. A computational method leveraging deep learning and molecular dynamics simulations enables the rapid discovery of antimicrobial peptides with low toxicity and with high potency against diverse Gram-positive and Gram-negative pathogens.

Broad-Spectrum Antiviral Peptides and Polymers.

Abstract: As the human cost of the pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still being witnessed worldwide, the development of broad-spectrum antiviral agents against emerging and re-emerging viruses is seen as a necessity to hamper the spread of infections. Various targets during the viral life-cycle can be considered to inhibit viral infection, from viral attachment to viral fusion or replication. Macromolecules represent a particularly attractive class of therapeutics due to their multivalency and versatility. Although several antiviral macromolecules hold great promise in clinical applications, the emergence of resistance after prolonged exposure urges the need for improved solutions. In the present article, the recent advancement in the discovery of antiviral peptides and polymers with diverse structural features and antiviral mechanisms is reviewed. Future perspectives, such as, the development of virucidal peptides/polymers and their coatings against SARS-CoV-2 infection, standardization of antiviral testing protocols, and use of artificial intelligence or machine learning as a tool to accelerate the discovery of antiviral macromolecules, are discussed.

Effects of Hydrophobicity on Antimicrobial Activity, Selectivity, and Functional Mechanism of Guanidinium-Functionalized Polymers.

Abstract: In this study, a series of guanidinium-functionalized polycarbonate random co-polymers is prepared from organocatalytic ring-opening polymerization to investigate the effect of the hydrophobic side chain (ethyl, propyl, isopropyl, benzyl, and hexyl) on their antimicrobial activity and selectivity. Although the polymers exhibit similar minimum inhibitory concentrations, the more hydrophobic polymers exhibit a faster rate of bacteria elimination. At higher percentage content (20 mol%), polymers with more hydrophobic side chains suffer from poor selectivity due to their high hemolytic activity. The highly hydrophobic co-polymer, containing the hydrophobic hexyl-functionalized cyclic carbonate, kills bacteria via a membrane-disruptive mechanism. Micelle formation leads to a lower extent of membrane disruption. This study unravels the effects of hydrophobic side chains on the activities of the polymers and their killing mechanism, providing insights into the design of new antimicrobial polymers.

Overcoming Barriers in Polycarbonate Synthesis: A Streamlined Approach for the Synthesis of Cyclic Carbonate Monomers

Abstract: Accessing cyclic carbonate monomers on a large scale is critical for the development of any new carbonate-based materials platform. The synthesis of carbonate monomers can be a challenging and tedi...

Exploring Reusability of Disposable Face Masks: Effects of Disinfection Methods on Filtration Efficiency, Breathability, and Fluid Resistance

Abstract: To curb the spread of the COVID-19 virus, the use of face masks such as disposable surgical masks and N95 respirators is being encouraged and even enforced in some countries. The widespread use of masks has resulted in global shortages and individuals are reusing them. This calls for proper disinfection of the masks while retaining their protective capability. In this study, the killing efficiency of ultraviolet-C (UV-C) irradiation, dry heat, and steam sterilization against bacteria (Staphylococcus aureus), fungi (Candida albicans), and nonpathogenic virus (Salmonella virus P22) is investigated. UV-C irradiation for 10 min in a commercial UV sterilizer effectively disinfects surgical masks. N95 respirators require dry heat at 100 degrees C for hours while steam treatment works within 5 min. To address the question on safe reuse of the disinfected masks, their bacteria filtration efficiency, particle filtration efficiency, breathability, and fluid resistance are assessed. These performance factors are unaffected after 5 cycles of steam (10 min per cycle) and 10 cycles of dry heat at 100 degrees C (40 min per cycle) for N95 respirators, and 10 cycles of UV-C irradiation for surgical masks (10 min per side per cycle). These findings provide insights into formulating the standard procedures for reusing masks without compromising their protective ability.

Building blocks to the future of regenerative medicine: Organoid bioprinting

Abstract: Despite being valuable models of study, organoids can be limited in their usefulness due to their small millimeter scale. In a letter in Nature Materials, Lutolf and his team at the Ecole Polytechnique Federale de Lausanne (EPFL) designed an innovative three-dimensional (3D) bioprinting concept that they termed bioprinting-assisted tissue emergence (BATE), overcoming organoids limits by using them as building blocks to mimic macroscale in vivo tissue. Their novel approach, combining the precision of bioprinting with the self-organizing potential of organoids, opens the path for new breakthroughs in regenerative medicine because of the potential of the engineered tissue to mimic native organ boundaries as well as tissue-tissue interactions.

Co 3 O 4 Nanowires Capable of Discharging Low Voltage Electricity Showing Potent Antibacterial Activity for Treatment of Bacterial Skin Infection

Abstract: Overuse of antibiotics has led to multidrug resistance (MDR) in bacteria, posing a tremendous challenge to the healthcare system. There is an urgent need to explore unconventional strategies to overcome this issue. Herein, for the first time, we report a capacitive Co3 O4 nanowire electrode coated on flexible carbon cloth, which is capable of eliminating bacteria while discharging, for the treatment of skin infection. Benefiting from the unique nanowire-like morphology, the Co3 O4 nanowire electrode with increased active sites and enhanced capacitive property exhibits a prominent antibacterial effect against both Gram-positive and Gram-negative bacteria after charged at a low voltage of 2 V for 30 min. Furthermore, the electrode is demonstrated to be recharged for multiple antibacterial treatment cycles without significant change of antibacterial activity, allowing for practical use in a non-clinical setting. More importantly, this Co3 O4 nanowire electrode is capable of damaging bacterial cell membrane and inducing the accumulation of intracellular ROS without impairing viability of skin keratinocytes. In a mouse model of bacterial skin infection, the Co3 O4 electrode shows significant therapeutic efficacy by eradicating colonized bacteria, thus accelerating the healing process of infected wounds. This nanostructured capacitive electrode provides an antibiotic-free, rechargeable, and wearable approach to treat bacterial skin infection. This article is protected by copyright. All rights reserved.

Potent Antiviral and Antimicrobial Polymers as Safe and Effective Disinfectants for the Prevention of Infections.

Abstract: Disinfection using effective antimicrobials is essential in preventing the spread of infectious diseases. This COVID-19 pandemic has brought the need for effective disinfectants to greater attention due to the fast transmission of SARS-CoV-2. Current active ingredients in disinfectants are small molecules that microorganisms can develop resistance against after repeated long-term use and may penetrate the skin, causing harmful side-effects. To this end, a series of membrane-disrupting polyionenes that contain quaternary ammoniums and varying hydrophobic components is synthesized. They are effective against bacteria and fungi. They are also fast acting against clinically isolated drug resistant strains of bacteria. Formulating them with thickeners and nonionic surfactants do not affect their killing efficiency. These polyionenes are also effective in preventing infections caused by nonenveloped and enveloped viruses. Their effectiveness against mouse coronavirus (i.e., mouse hepatitis virus-MHV) depends on their hydrophobicity. The polyionenes with optimal compositions inactivates MHV completely in 30 s. More importantly, the polyionenes are effective in inhibiting SARS-CoV-2 by >99.999% within 30 s. While they are effective against the microorganisms, they do not cause damage to the skin and have a high oral lethal dose. Overall, these polyionenes are promising active ingredients for disinfection and prevention of viral and microbial infections.

Cationic polymer synergizing with chemotherapeutics and re-purposing antibiotics against cancer cells

Abstract: Chemotherapy is one of the most effective treatments for cancer. However, toxicity and the development of drug resistance have become the major hurdles to the commonly used chemotherapeutics such as doxorubicin and paclitaxel. Antibiotics have also been used as anti-cancer drugs due to their anti-proliferative and cytotoxic effects. However, these anti-tumor antibiotics like ciprofloxacin face the similar resistance and toxicity issues. In this study, we used a quaternary ammonium-functionalized cationic polycarbonate to synergize with the existing chemotherapeutics and re-purpose antibiotics to address the resistance and toxicity issues. When used in combination with the drugs, the cationic polymer induced 2-3 fold more damage in the cancer cell membrane within 2 hours, thus enhancing the uptake of chemotherapeutics up to 2.5 fold more into the breast, liver and even chemotherapeutics-resistant cancer cells. On the other hand, the chemotherapeutics increased the cellular uptake of polymer. The combined effects resulted in 3-10 fold reduction in IC50 of chemotherapy drugs and yielded therapeutic synergy at a clinically-relevant concentration range of drugs when treating multiple types of cancer cells, while the use of guanidinium-functionalized polymer capable of membrane translocation did not lead to a synergistic effect. Thus, the quaternary ammonium-functionalized cationic polymer can increase the therapeutic efficacies of existing drugs, mitigating toxicities by lowering required dosage and circumventing drug resistance via its membrane disruption mechanism. The findings of this study provide insights into designing future anticancer therapy.

Elucidating the anticancer activities of guanidinium-functionalized amphiphilic random copolymers by varying the structure and composition in the hydrophobic monomer.

Abstract: Rationale: Use of traditional anticancer chemotherapeutics has been hindered by the multifactorial nature of multi-drug resistance (MDR) development and metastasis. Recently, cationic polycarbonates were reported as novel unconventional anticancer agents that mitigated MDR and inhibited metastasis. The aim of this study is to explore structure-anticancer activity relationship. Specifically, a series of cationic guanidinium-based random copolymers of varying hydrophobicity was synthesized with a narrow polydispersity (Ð = 1.12-1.27) via organocatalytic ring-opening polymerization (OROP) of functional cyclic carbonate monomers, and evaluated for anticancer activity, killing kinetics, degradability and functional mechanism. Methods: Linear, branched and aromatic hydrophobic side chain units, such as ethyl, benzyl, butyl, isobutyl and hexyl moieties were explored as comonomer units for modulating anticancer activity. As hydrophobicity/hydrophilicity balance of the polymers determines their anticancer efficacy, the feed ratio between the two monomers was varied to tune their hydrophobicity. Results: Notably, incorporating the hexyl moiety greatly enhanced anticancer efficiency and killing kinetics on cancer cells. Degradation studies showed that the polymers degraded completely within 4-6 days. Flow cytometry and lactate dehydrogenase (LDH) release analyses demonstrated that anticancer mechanism of the copolymers containing a hydrophobic co-monomer was concentration dependent, apoptosis at IC50, and both apoptosis and necrosis at 2 × IC50. In contrast, the homopolymer without a hydrophobic comonomer killed cancer cells predominantly via apoptotic mechanism. Conclusion: The hydrophobicity of the polymers played an important role in anticancer efficacy, killing kinetics and anticancer mechanism. This study provides valuable insights into designing novel anticancer agents utilizing polymers.

Polymere mit antimikrobiellen Funktionalitäten

Abstract: Polymer, aufweisend:eine lonen-Wiederholungseinheit, aufweisend ein Kation, das entlang eines abbaubaren Gerusts verteilt ist, wobei das abbaubare Gerust eine Terephthalamidstruktur aufweist, wobei die lonen-Wiederholungseinheit antimikrobielle Funktionalitat aufweist, wobei die lonen-Wiederholungseinheit eine Struktur aufweist, die durch Formel 1 gekennzeichnet ist:wobei X das Kation ist, wobei R die hydrophobe funktionelle Gruppe ist, wobei n eine ganze Zahl groser als oder gleich zwei und kleiner als oder gleich eintausend ist undwobei Y eine funktionelle Gruppe ausgewahlt aus einer Gruppe bestehend aus einer Estergruppe und einer Carbonylgruppe ist.