Answer by Tirumalai Kamala:
Several types of nanoparticles, namely, liposomes, polymeric nanoparticles, solid lipid nanoparticles, dendrimers, appear to be taken up by bacteria. These structures have been explored mainly for their capacity to more efficiently deliver antibiotics. I highlight the few studies that directly compared bacterial uptake/activity of ‘nanoparticled’ cargo versus cargo alone. Key details that enhance bacterial nanoparticle uptake are italicized.
Liposomes are small spherical vesicles with phospholipid bilayer walls, usually composed of an amphipathic lipid such as phosphatidylcholine. Incorporating cholesterol increases the membrane’s rigidity. Liposomes encapsulate an aqueous space ranging from about 30 to 10000 nm in diameter.
Liposomes directly fuse with bacterial membranes, releasing their contents either within the bacterial cell membranes or into its interior. This can improve antibiotic delivery into the bacterial cells, side-stepping bacterial drug-resistance mechanisms such as bacterial membrane impermeability/low permeability or efflux systems (3).
Cationic liposome formulations bind more efficiently to skin-associated bacteria, Staphylococcus epidermidis and Proteus vulgaris (4).
Liposome-encapsulated oleic acid was bactericidal against MRSA at a 12-fold lower concentration (5) compared to free oleic acid.
Liposome-encapsulated Polymyxin B or vancomycin and teichoplanin had better antibacterial activity against drug-resistant Pseudomonas aeruginosa and MRSA, respectively (1). These liposomes also caused bacterial membrane lipid deformation suggesting they fused with it.
Skin-associated Propionibacterium acnes (P. acnes). Lauric acid, a free fatty acid showed stronger anti-bacterial activity compared to palmitic and lauric acid. However, lauric acid is poorly water soluble, which limits its use in acne treatment. A study of lauric acid liposome formulation (LipoLA) showed it fused with P. acnes membranes, releasing lauric acid within and killing the bacteria (6).
Metal liposomes: Metal matters. Platinum, zinc and titanium enter bacteria, gold doesn’t.
Wang et al made 16 nm gold nanospheres stabilized with citrate ions, which adhered well with the Salmonella typhimurium surface but were unable to get into the bacteria (7). A comparison of gold and platinum nanoparticles (8) showed the former interacted with Salmonella enteritidis but did not get inside, whereas platinum nanoparticles were observed inside the bacteria.
Using flow cytometry (9), dynamic light scattering and transmission electron microscopy (10), Ashutosh et al found that Salmonella typhimurium directly uptake zinc and titanium nanoparticles.
Key detail? A mammalian liver component called S9 enhances this metal nanoparticle uptake by bacteria. Experimental studies used either rat- or mouse-liver derived fraction S9. What is the role of this liver S9 fraction? It could supplement metabolic enzymes such as cytochrome P450 (10), enhance the formation of nanoparticle micelles facilitating uptake (11) or serve as a protein coating for the nanoparticles, again facilitating uptake (12).
I won’t cover silver nanoparticles since ionic silver is largely toxic to bacteria, and used as an antimicrobial agent itself.
Zhang, L., et al. (1) describe the advantages of polymeric nanoparticles for bacterial delivery
- They are structurally stable and can be synthesized with greater size precision.
- They have functional groups that can be chemically modified. Lectin, a protein that binds to bacterial cell wall carbohydrates, is frequently used for targeted antimicrobial delivery of polymeric nanoparticles. Lectin-conjugated polymeric nanoparticles containing gliadin specifically bound to Helicobacter pylori cell wall carbohydrate receptors and released the antimicrobial agent into the bacteria (13).
Zhang et al describe two major types of polymeric nanoparticles for antimicrobial drug delivery. One is formed via spontaneous self-assembly of diblock copolymers consisting of hydrophilic and hydrophobic parts. The hydrophobic part forms the polymeric core holding the cargo while the hydrophilic part protects the core from degradation. The length of the hydrophobic chain controls the rate of cargo release. Biodegradable polymers such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactide-co-glycolide) (PLGA), poly (?-carprolactone) (PCL), and poly(cyano- acrylate) (PCA) are used to form the hydrophobic polymeric core, while polyethylene glycol (PEG) is most commonly used as the hydrophilic part. The hydrophobic nature of the nanoparticle core allows polymeric nanoparticles to carry and deliver poorly water soluble cargo.
In the other type of polymeric nanoparticle, linear polymers such as polyalkyl acrylates and polymethyl methacrylates form nanocapsules by emulsion polymerization. The cargo, antibiotics for example, are either absorbed or covalently conjugated to the nanoparticle surface.The caveat with covalent linkage is the need to empirically assess case-by-case whether the linkage inactivates cargo activity. For example, Abeylath et al found that covalent linkage inactivated penicillin but not beta-lactam or ciprofloxacin (14).
Nanoparticles using poly (lactide-co-glycolide) [PLGA] loaded with antibiotics such as gentamicin (15), azithromicin and clarithromicin (16, 17) were more effective than corresponding intact antibiotic against Salmonella typhimurium. It’s possible this is due to such nanoparticles adhering better to the bacteria. Dillen et al reported adhesion of PLGA containing cationic Eudragit nanoparticles to S. aureus (18). Bacterial cell walls tend to be negatively charged (19) so exploiting such electrostatic interactions helps bacterial nanoparticle uptake (20). PLGA has many other advantages including low toxicity, cargo flexibility, easy synthesis, precision engineering for surface properties (20).
Solid lipid nanoparticles
Lipid + surfactants for emulsification. Lipids can be free fatty acids such as palmitic, decanoic or behenic acids, or triglycerides such as trilaurin, trimyristin, or tripalmitin, or steroids such as cholesterol. Emulsifiers include soybean lecithin, phosphatidylcholine. Solid lipid nanoparticles have many advantages over other nanoparticles including greater cargo stability, bothhydrophilic and lipophilic cargo can be loaded, no need for organic solvents, greater precision in controlled cargo release and targeting, and improved bulk production.
A dendrimer is a polymer structure with enhanced surface area-to-volume ratio owing to extensive branching around a core unit. When a dendrimer has a high concentration of positively charged quaternary ammonium compounds on its surface, they bind more efficiently to negatively charged microbial cell walls. This increases bacterial membrane permeability, letting more dendrimers inside the bacteria (1, 21).
I could not find a single study that directly compared cargo alone versus solid lipid nanoparticle- or dendrimer-encapsulated cargo uptake by bacteria.
- Zhang, L., et al. “Development of nanoparticles for antimicrobial drug delivery.” Current medicinal chemistry 17.6 (2010): 585-594
- Nokhodchi, Ali, Ghobad Mohammadi, and Taravat Ghafourian. Nanotechnology tools for efficient antibacterial delivery to Salmonella. INTECH Open Access Publisher, 2012
- Mugabe, Clement, et al. “Mechanism of enhanced activity of liposome-entrapped aminoglycosides against resistant strains of Pseudomonas aeruginosa.” Antimicrobial agents and chemotherapy 50.6 (2006): 2016-2022
- Robinson, Anne M., et al. “The interaction of phospholipid liposomes with mixed bacterial biofilms and their use in the delivery of bactericide.” Colloids and Surfaces A: Physicochemical and Engineering Aspects 186.1 (2001): 43-53.
- Huang, Chun-Ming, et al. “Eradication of drug resistant Staphylococcus aureus by liposomal oleic acids.” Biomaterials 32.1 (2011): 214-221
- Yang, Darren, et al. “The antimicrobial activity of liposomal lauric acids against Propionibacterium acnes.” Biomaterials 30.30 (2009): 6035-6040.
- Wang, Shuguang, et al. “Toxic effects of gold nanoparticles on Salmonella typhimurium bacteria.” Toxicology and industrial health (2011): 0748233710393395
- Sawosz, Ewa, et al. “Visualization of gold and platinum nanoparticles interacting with Salmonella enteritidis and Listeria monocytogenes.” International journal of nanomedicine 5 (2010): 631
- Kumar, Ashutosh, et al. “A flow cytometric method to assess nanoparticle uptake in bacteria.” Cytometry Part A 79.9 (2011): 707-712
- Kumar, Ashutosh, et al. “Cellular uptake and mutagenic potential of metal oxide nanoparticles in bacterial cells.” Chemosphere 83.8 (2011): 1124-1132
- Sereemaspun, A., et al. “Inhibition of Human Cytochrome P450 Enzymes by Metallic Nanoparticles: A preliminary to Nanogenomics.” International Journal of Pharmacology 4.6 (2008).
- Romberg, Birgit, Wim E. Hennink, and Gert Storm. “Sheddable coatings for long-circulating nanoparticles.” Pharmaceutical research 25.1 (2008): 55-71
- Umamaheshwari, R. B., and N. K. Jain. “Receptor mediated targeting of lectin conjugated gliadin nanoparticles in the treatment of Helicobacter pylori.” Journal of drug targeting 11.7 (2003): 415-424.
- Abeylath, Thotaha Wijayahewage Sampath Chrysantha. “Glyconanobiotics: Novel carbohydrated nanoparticle polymers.” (2007)
- Ranjan, Ashish, et al. “Antibacterial efficacy of core-shell nanostructures encapsulating gentamicin against an in vivo intracellular Salmonella model.” International journal of nanomedicine 4 (2009): 289
- Mohammadi, Ghobad, et al. “Development of azithromycin–PLGA nanoparticles: Physicochemical characterization and antibacterial effect against Salmonella typhi.” Colloids and Surfaces B: Biointerfaces 80.1 (2010): 34-39.
- Mohammadi, Ghobad, et al. “Physicochemical and anti-bacterial performance characterization of clarithromycin nanoparticles as colloidal drug delivery system.” Colloids and Surfaces B: Biointerfaces 88.1 (2011: 39-44).
- Dillen, Kathleen, et al. “Adhesion of PLGA or Eudragit®/PLGA nanoparticles to Staphylococcus and Pseudomonas.” International journal of pharmaceutics 349.1 (2008): 234-240.
- Al-Kobaisi, Muhannad F. “Jawetz, Melnick & Adelberg’s Medical Microbiology.” Sultan Qaboos University Medical Journal 7.3 (2007): 273.
- Radovic-Moreno, Aleksandar F., et al. “Surface charge-switching polymeric nanoparticles for bacterial cell wall-targeted delivery of antibiotics.” ACS nano 6.5 (2012): 4279-4287
- Huh, Ae Jung, and Young Jik Kwon. ““Nanoantibiotics”: a new paradigm for treating infectious diseases using nanomaterials in the antibiotics resistant era.” Journal of Controlled Release 156.2 (2011): 128-145.