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Use of nanotechnology in antimicrobial R&D- Students Against (SAS) Superbugs Africa Workshop
- 1. Advances in Antimicrobial Research and Development Presented by Faith Zablon North Carolina A and T State University, USA Introductory talk on the Use of nanotechnology in antimicrobial drugs research and discovery
- 2. What do we know about AMR …..? • A global pandemic – 700,000 deaths yearly • Underuse or Excess use • Spillage into the environment (Animals, plants, water, and aquatic life) – it’s a cycle • Adverse socio-economic impacts
- 4. Faith Z. on Biorender Antimicrobial activity Mechanisms of resistance are: • Limiting uptake of a drug • Modification of a drug target • Inactivation of a drug • Active efflux of a drug.
- 5. 1. Synergistic approach and Combined antimicrobial therapy 2. Drug repurposing 3. Use of Nanotechnology - Nanoparticles Strategies for Tackling AMR options Improved diagnostics Effective health education Better antimicrobial stewardship Clinical research Antibiotic review kit
- 6. Nanomaterials tackling antimicrobial development Nanomaterials as self-therapeutic agents and drug-delivery vehicles for antimicrobial therapies
- 7. • Diagnostic platforms • As antimicrobials • Drug delivery systems • Improve the efficacy of antimicrobials Functions of nanomaterials in AMR The nanomaterials are classified into various categories: 1. Carbon-based nanomaterial 2. Inorganic nanomaterial 3. Organic-based nanomaterial Classification of Nanomaterials for applications in antimicrobials https://www.frontiersin.org/articles/10.3389/fchem.2019.00872/full
- 8. 1. Unique physiochemical properties - similar in size scale to biomolecular and bacterial cellular systems, enabling additional multivalent interactions as compared to small molecule antibiotics 2. Large surface area enables multivalent interactions with bacteria along with high cargo loading 3. Nanomaterials can, with appropriate engineering, overcome common bacterial drug resistance mechanisms such as overexpression of efflux pumps Properties of nanomaterials Properties of NPs that favor application in antimicrobial approaches • Size • Surface modification • Biocompatibility • Biosorption – hydrophilicity/hydrophobicity • Nanoparticle breakdown • Cellular uptake
- 10. Faith Z. on Biorender DLS NTA SEM TEM UV-Vis spectrophotometer XPS
- 11. Uses of Nanoparticles Nanoparticles (NPs) are small (nano), robust, and advanced chemical tools to diagnose and treat diseases. They combat bacteria by inducing cell toxicity mechanisms They also act as a medium for carrying and transporting antimicrobials
- 12. Modifications of Nanomaterials that favor applications in antimicrobial therapy Non-functionalized nanomaterials often exhibit narrow-spectrum activity against bacterial species; display low therapeutic indices (i.e., selectivity) against healthy mammalian cells, limiting their widespread use in biomedical applications. The surface chemistry of nanomaterials is critical to modulate their interaction with bacteria, improving their broad- spectrum activity while simultaneously reducing their toxicity against mammalian cells.
- 13. Nanomaterials as antimicrobials Carbon nanotubes Fullerenes Graphene Membrane stress and cell content release by single-walled nanotubes Induce oxidative stress that disrupts cell wall and DNA Graphene oxide nanosheets are hydrophilic; absorption into cells allows RNA efflux that disrupts the cell membrane of bacteria; gram +ve/-ve Carbon-based Nanomaterials
- 14. Gold Nanoparticles • Favored by the chemical stability • Electrostatic effect on the cell membrane based on charge • Near infra-red (NIR) light absorbed by Au, particles treat bacteria infections • Synergistic coupling with antimicrobials proves effective, e.g., with streptomycin (streptomycin-Au) • Coupling with nanocomposites like chitosan and ampicillin has antimicrobial activity
- 15. • Target cell division • Respiratory chain by triggering reactive oxygen stress • Sulfur and nitrogen affinity that destroys bacterial structure by binding to thiol and amino groups • Synergistic effect in combination with antimicrobials, e.g, vancomycin Silver Nanoparticles
- 16. Zinc oxide and titanium oxide Nanoparticles Sirelkhatim, A et al., 2020
- 17. Liposomes and micelles for antimicrobial drug delivery
- 18. Research based evidences of nanomaterials for antimicrobial use NOTE: Antibiotic capped NPs exhibited high antibacterial efficacy against Gram-positive and Gram-negative bacterial species. a. AuNPs were conjugated with bis(vancomycin) Synergistic activity of AgNPs with ampicillin (Amp) against bacteria Shvedova AA et al, 2012
- 19. Challenges of using nanomaterials as antimicrobials and drug delivery systems • Cost • Cytotoxicity • Stability • Reproducibility • Reduced efficiency
- 20. References: 1. Antibacterial Carbon-Based NanomaterialsQi Xin, Hameed Shah, Asmat Nawaz, Wenjing Xie, Muhammad Zain Akram, Aisha Batool, Liangqiu Tian, Saad Ullah Jan, Rajender Boddula, Beidou Guo, Qian Liu, Jian Ru Gong 2. Avila, S.R.R., Schuenck, G.P.D., Silva, L.P.C.e. et al. High antibacterial in vitro performance of gold nanoparticles synthesized by epigallocatechin 3-gallate. Journal of Materials Research 36, 518–532 (2021). https://doi.org/10.1557/s43578-020-00012-5 3. Mubeen B, Ansar AN, Rasool R, Ullah I, Imam SS, Alshehri S, Ghoneim MM, Alzarea SI, Nadeem MS, Kazmi I. Nanotechnology as a Novel Approach in Combating Microbes Providing an Alternative to Antibiotics. Antibiotics (Basel). 2021 Nov 30;10(12):1473. doi: 10.3390/antibiotics10121473. PMID: 34943685; PMCID: PMC8698349. 4. Yaqoob, S. B., Adnan, R., Rameez Khan, R. M., & Rashid, M. (2019). Gold, Silver, and Palladium Nanoparticles: A Chemical Tool for Biomedical Applications. Frontiers in Chemistry. https://doi.org/10.3389/fchem.2020.00376 5. Sirelkhatim, A., Mahmud, S., Seeni, A. et al. Review on Zinc Oxide Nanoparticles: Antibacterial Activity and Toxicity Mechanism. Nano-Micro Lett. 7, 219–242 (2015). https://doi.org/10.1007/s40820-015-0040-x 6. Fayaz, A. M., Balaji, K., Girilal, M., Yadav, R., Kalaichelvan, P. T., & Venketesan, R. (2010). Biogenic synthesis of silver nanoparticles and their synergistic effect with antibiotics: a study against gram-positive and gram-negative bacteria. Nanomedicine: Nanotechnology, Biology and Medicine, 6(1), 103-109. https://doi.org/10.1016/j.nano.2009.04.006 7. Gupta A , Mumtaz S , Li CH , Hussain I , Rotello VM . Combatting antibiotic-resistant bacteria using nanomaterials. Chem Soc Rev. 2019 Jan 21;48(2):415-427. doi: 10.1039/c7cs00748e. PMID: 30462112; PMCID: PMC6340759. 8. Wang, D., Ren, Y., Busscher, H. J., & Shi, L. (2019). Lipid-Based Antimicrobial Delivery-Systems for the Treatment of Bacterial Infections. Frontiers in Chemistry. https://doi.org/10.3389/fchem.2019.00872 9. {Zhu2013PhysicochemicalPD, title={Physicochemical properties determine nanomaterial cellular uptake, transport, and fate.}, author={Motao Zhu and Guangjun Nie and Huan Meng and Tian Xia and Andre E. Nel and Yuliang Zhao}, journal={Accounts of chemical research}, year={2013}, volume={46 3}, pages={ 622-31 } }
Editor's Notes
- By 2050, it will kill over 10 million a year Pharmaceutical companies close down due to a lack of financial incentives; antibiotic production is non-profitable to companies
- The Antibiotic resistance in bacteria develops through the mechanisms shown in Figure 3: Antibiotic enzyme inactivation/degradation; an endogenous cellular enzyme is modified to interact with that of the antibiotic in a manner in which the bacteria are no longer affected. B-lactamase enzymes are among the most important examples; they hydrolyze most commonly administered antibiotics, i.e., b-lactams (cephalosporin and penicillin), and are the most widespread source of antibiotic resistance in Gram-negative bacteria. The excretion of the drug through efflux pumps; Bacteria are triggered to eliminate the antibiotic by stimulating the proteins that can eradicate an extensive range of substances from the periplasm to the outside cell. This is a mechanism of resistance especially essential for P. aeruginosa and Acinetobacter spp. Reduced absorption by variations in the external membrane permeability; these changes inhibit the successful entry of antibiotics. Drug target modifications to weaken or demolish the antibiotic binding efficacy and thereby minimize its potential. Mode of action of antibiotics. Cell wall synthesis Inhibition Folic acid metabolism Inhibition Disruption of Cell Membranes. DNA Gyrase Inhibition of RNA elongation RNA synthesis inhibitors Protein Synthesis Inhibitors (50S inhibitor) Protein Synthesis Inhibitors (30S Inhibitor) Inhibition of Protein Synthesis (tRNA).
- Summary of the published evidence for the effectiveness and safety of shorter antibiotic courses in hospitalised patients. Analysis of existing electronic hospital data on antibiotic prescribing and on patients’ outcomes, to check that there is no other evidence that stopping antibiotics could harm patients. Interviews with healthcare professionals and patients/carers to understand better their perceptions and experiences of antibiotic prescribing, and to identify potential barriers to changing current practice. Development of the ‘Antibiotic Review Kit’. The package includes an internet-based education tool, a new way of categorising antibiotic prescriptions to help doctors and other healthcare professionals review patients and materials for patients themselves. Clinical trial to test the Antibiotic Review Kit in up to 36 hospitals, comparing what happens before and after its introduction. Study of how healthcare professionals weigh up the costs and benefits of reducing antibiotic use, and the cost-effectiveness of the Antibiotic Review Kit.
- Nanoparticles are being used in therapeutic approaches and target delivery of drugs, prognostic monitoring, tumor identification in cancer. Synthesis of these NP: Physical vapor deposition, Laser ablations, Sputtering, green methods, chemical methods e.g., photo-reduction, microemulsion. Most of these methods can produce highly toxic NP coated with compounds that increase toxicity levels. But the green method, which synthesizes these materials from the biomass-based surface coating, provides more stable, less toxic NPs, with active surface areas for biological interactions.
- NPs act by combating bacteria and AMR, and they also act as a medium and carrier for antibiotics
- Factors to consider when functionalizing the surfaces of NPs: Size, hydrophobicity, hydrophilicity, application NPs that are rod-shaped have more effective than NPs with a spherical shape: smaller size and higher surface area to volume ratio
- free Cu2+ions from copper NPs can generate reactive oxygen species (ROS) that disrupt amino acid synthesis and DNA in bacterial cells A carbon nanotube is a tube made of carbon with diameters typically measured in nanometers. Single-wall carbon nanotubes are one of the allotropes of carbon, intermediate between fullerene cages and flat graphene, with diameters in the range of a nanometre.
- Ag in antimicrobials is used to treat wound injuries, surgical device coating The silver ions disrupt the bacterial membrane and electron transport while simultaneously causing DNA damage
- ZnO and TiO2 based nanomaterials cause cell membrane damage and generate ROS to kill bacteria
- The ability of liposomes to fuse with the outer membrane of bacteria due to the fluidity of their phospholipid bilayer structure. The liposomal phospholipid bilayer resembles the structure of bacterial cell membranes, which facilitates fusion based on similarity. Upon fusion, high antimicrobial doses are directly available inside a bacterium. NOTE: There are different types of liposomes, such as natural lipid liposomes, cationic liposomes, anionic liposomes
- In this study, ~5 nm AuNPs were conjugated with bis(vancomycin) cystamide through Au-S bond resulting in ~61 vancomycin molecules per NP