Food borne diseases are responsible for almost 1 in 10 illnesses globally as per World Health Organization’s (WHO) 2005 report. Salmonella is a pathogenic bacterium ubiquitous to diverse habitats and a causative organism for 1 out of 4 diarrheal diseases worldwide. The bacterium has evolved to survive the acids present in the human gastrointestinal tract. Moreover, in order to pass the intestinal barrier, many typhoidal variants of the bacterium hide in the macrophages (type of immune cells) of our body, to be trafficked to the rest of the body.
Today, a major challenge in addressing bacterial infections is drug resistance -- most bacteria develop resistance to antibiotics, rendering antibiotics ineffective to treat the disease. Due to the emergence of multidrug resistance (MDR) in Salmonella, many antibiotics such as Chloramphenicol, Ampicillin etc. are no longer prescribed. Current lot of antibiotics- Ceftriaxone or Ciprofloxacin have as well gradually started showing signs of decreased susceptibility.
In these times of uncertainty, nanocarriers offer a ray of hope due to their ability to hide drugs within and bypass as a ‘Trojan Horse’, thereby requiring much lower dose of antibiotics needed than when administered with oral antibiotics alone.
In a recent study, scientists from the Indian Institute of Science (IISc), Bangalore, have used mesoporous silica nanoparticles (MSN) for their high porosity, ease of attaching bio-molecules on the surface and stability in biological fluids like blood and lymph. The idea for research was inspired by a particularly interesting case of Salmonella infection, says Prof. Ashok Raichur, who led the study along with Prof. Dipshikha Chakravortty.
The essential amino acid arginine mediates immune response in macrophages. “Salmonella is known to deprive the host cell of the arginine amino acid for metabolism and prevent host cell induced damage”, explains Prof. Raichur. Since arginine protects Salmonella from an acidic stomach environment, the researchers have developed nanocarriers that target these macrophages. “We synthesized arginine decorated nanocarriers containing the antibiotic to effectively target the pathogen lurking deep inside the cell, which otherwise would not have been possible using conventional antibiotic therapy, because the intracellular antibiotic concentration would not be sufficient to kill the pathogen”, he explains
Arginine was coated on the surface of silica nanoparticles that were loaded with the antibiotic Ciprofloxacin. These nanoparticles were shown to be preferentially picked by cells infected with Salmonella typhimurium in laboratory testing. The researchers tested these nanocarriers on mice three days after they were infected with Salmonella infection. The nanocarriers with Ciprofloxacin showed improved antibacterial efficacy by 3-4 times in comparison to the drug Ciprofloxacin administered alone.
In addition, there was significant reduction in the side effects due to the antibiotic treatments. While those mice that were administered Ciprofloxacin orally showed spleen enlargement (splenomegaly), the ones treated with nanocarriers showed marked reduction in weight and least inflammation in spleen.
“The antibiotic agent release was also controlled by using polyelectrolyte barriers to ensure a higher antibiotic payload delivery inside the infected cell, which is not possible in conventional therapy without increasing the dose of the antibiotic”, says Prof. Raichur. The promising outcomes were resultant of “coupled approach of antibiotic delivery and arginine enhanced host defence mechanism.”
When the researchers treated mice after 5 days post Salmonella infection to mimic advanced stage of infection, they observed a 100% survival rate of mice treated with the new nanocarriers as opposed to just 40% survival of those treated with Ciprofloxacin alone. Since the disease burden is more pronounced in patients over 60 years of age, the researchers conducted the same test on 52-week-old mice. They observed a 50% mortality rate in mice treated with new nanocarriers while administering Ciprofloxacin alone resulted in 100% mortality.
But can the nanocarrier formulation be used against other pathogens such as Shigella or Listeria? “The most attractive part of the nanocarrier lies in the flexibility it affords to attach different kinds of targeting agent. Hence, we are now looking at linking other molecules for treatment as well”, signs off Prof. Raichur.