Systems for Treatment of Bacterial Infections Developed Using Lipid-Based Antimicrobial Delivery

Posted on February 06, 2020


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One of the largest threats to mankind is hard-to-treat, antibiotic-resistant infectious biofilms. In fact, they’re expected to become the number one cause of death in just 30 short years. Why are they such a threat? Infectious biofilms are tenacious by nature, and antimicrobials have a hard time penetrating the biofilm matrix embedding its bacterial inhabitants. The biofilm matrix is composed of Extracellular Polymeric Substances, or EPS, containing proteins, polysaccharides, humic acids, and eDNA. It acts as a sort of glue that holds biofilm bacteria together, as well as protects them against the host immune system and environmental challenges.

The Challenges

The overuse of antibiotics has contributed to this problem as well—it’s led to the evolution of new antibiotic-resistant strains that can’t be killed by antibiotics we know of today. To worsen the problem, the development of new antibiotics is stalling. The time period during which they’re effective, and before the first resistant strains of bacteria arise, is growing shorter. The result is decreased incentive for commercialization, and therefore clinical use, of new antibiotics.

The first solution to develop is an antimicrobial or antimicrobial delivery system that allows the antimicrobial to penetrate deeply enough into the biofilm to kill it—that means penetrating across the entire thickness of the biofilm. Over the past few decades, a lot of nanotechnology-based drugs and delivery systems have been created to solve a separate, but similar problem. They self-target, penetrate, and eradicate tumors. While tumors and biofilms are, of course, very different, they share some important similarities:

  • Low pH environment
  • Similar problems encountered in clinical treatment
    • Prevention of resistance
    • Prevention of recurrence

As a result, new strategies for infection control are arising—ones that are derived from technologies originally designed for tumor treatment.

Where Do Lipids Come In?

Nanotechnology-derived antimicrobial delivery systems have excellent biocompatibility and can be made to be environmentally responsive and self-targeting—as long as their diameter is below the limit for reticuloendothelial rejection of around 100-200 nm. Without suitable functionalization of their outermost surface, however, their antimicrobial efficacy is typically quite low.

The two most common nanocarriers considered for drug loading? Micelles and lipid-based liposomes. Because of their amphiphilic nature, liposomes can be assembled into bilayers, which mimic the structure and composition of cell membranes. The main differentiating factor between micelles and liposomes is the hydrophilicity of their inner cores and outer surfaces. The hydrophilic head of the lipids determines the surface properties of liposomes, while the tail determines the fluidity of liposomal membranes.

In addition, micelles can only be loaded with hydrophobic antimicrobials—of which there aren’t many candidates. On the other hand, hydrophobic or amphiphilic antimicrobials can be inserted in the phospholipid bilayer. The number of candidate antimicrobials for liposome loading is relatively large, and the loading capacity is relatively high.

The fusogenicity, or ability to fuse with the outer membrane of bacteria, of lipid-based antimicrobial delivery systems is another big advantage. After fusion, high antimicrobial doses are directly available inside the bacterium.

Common Problems Using Antimicrobials

The elimination of infectious biofilms is an incredibly complex process. Since Van Leeuwenhoek noticed that the vinegar he used to clean his teeth killed only the bacteria residing at the outside of the biofilm (leaving the ones inside alive), there has been no adequate treatment. The main struggle? The penetration, accumulation, and eventual killing of antimicrobials over the entire thickness of an infectious biofilm. Antimicrobials have the potential to be enzymatically deactivated on their way to a biofilm in the blood circulation, once inside the biofilm. These problems all together make it impossible to kill bacteria in the necessary depth in biofilm. Essentially, this means the recurrence of the infection after treatment.

Once accumulated inside a biofilm, the antimicrobial has two actions it can perform:

  • It can generate cell wall damage to the biofilm
  • It can enter a bacterium to interfere with vital metabolic processes

Both of these actions are difficult, especially considering how many protective mechanisms bacteria have developed over time. Bacteria can even seek shelter against antimicrobials in mammalian cells, where antimicrobials can’t go—making fulfilling their duties that much more difficult.

Solutions Offered by Liposomal Antimicrobial Nanocarriers

Several Gram-negative and Gram-positive bacterial strains have been proven to be susceptible to antibiotics when encapsulated in a liposomal nanocarrier—even if they’ve been previously resistant to a specific antibiotic free in solution. This is, arguably, the most important advantage of liposomes over other nanocarriers.

The fusogenicity of liposomes can also significantly improve the antibacterial activity of antibiotics. In studies, liposomes with enhanced fusogenicity, possessing cholesterol hemisuccinate and loaded with vancomycin for example, had much lower minimal inhibitory concentrations than vancomycin free in solution against a variety of Gram-negative bacterial strains, that would be considered vancomycin-resistant based on their MIC.

In addition to this, fusogenic liposomes composed of dipalmitoylphosphatidylcholine and dimyristoylphosphatidylglycerol in a ratio of 18:1, and loaded with tobramycin, eradicated a mucoid chronic, pulmonary Pseudomonas aeruginosa infection. In contrast, tobramycin free in solution was not effective. For more of the latest industry news and products, visit Avanti’s website today.