Cornell researchers have identified an antibiotic, rifampin, that is 99.9% effective against Salmonella Typhi, the bacterium that causes typhoid fever. Researchers also predict that rifampin will work on other life-threatening diseases like bacterial pneumonia and meningitis.
Strains of S. Typhi that are resistant to multiple drugs claim over 150,000 lives globally every year. The researchers' results, published June 4 in eBioMedicine, show that the likelihood of encountering rifampin-resistant typhoid cases is less than 1 in every 1,000 cases.
"Our study shows that rifampin would be one solution if there are very severe or difficult cases such as hypervirulent S. Typhi infections that are also multidrug-resistant," said Jeongmin Song, coauthor of the research and associate professor in the Department of Microbiology and Immunology at the College of Veterinary Medicine. "We hope that some doctors in the affected countries implement our finding to treat their patients."
Rifampin is a drug approved by the Food and Drug Administration, on the World Health Organization's model list of essential medicines and is used for treating traveler's diarrhea. That means that the practical use of rifampin to treat typhoid fever patients could happen soon.
"I think one reason rifampin was overlooked as a possible treatment against typhoid fever could be the emergence of rifampin-resistant tuberculosis cases," Song said. "Luckily, we found that over 99.4% of S. Typhi clinical isolates are still susceptible to two antibiotics: rifampin and azithromycin." For rifampin specifically, that number goes up to 99.91%.
Song and postdoctoral researcher Gi Young Lee discovered that rifampin works by removing the outer layer of the bacteria, called the capsule, that serves as a protective cloak against the host's immune system.
The capsule plays a critical role in bacteria's ability to infect hosts, evade the immune system, form a biofilm and interfere with antibiotic penetration. The type of capsule found in S. Typhi is called Vi. The variant hyper-Vi tends to have a higher mortality rate and is often linked to resistance to antibiotics.
The team was excited to see that rifampin removes the capsule in hyper-Vi variants, Song said. "That, in turn, made S. Typhi susceptible to clearance by the immune system." This means that hosts can eliminate decapsulated S. Typhi more easily, and have a higher survival rate.
Many medically important bacterial pathogens are capsulated. The genetic data Song and Lee produced indicate that the rifampin decapsulation mechanism is broadly applicable to other bacterial pathogens with a biologically similar capsule. "Based on our data, rifampin is likely to remove capsular polysaccharides of other encapsulated pathogens, too," Song said.
Connecting this research and her recently published work on the typhoid toxin - another important mechanism S. Typhi uses to infect and thrive in its hosts - Song is now planning to investigate different combinations of decapsulation drugs and anti-typhoid toxin drugs.
"Our goal is to find out which drugs block the actions of these two virulence factors and offer more treatment options against S. Typhi infections."
Elodie Smith is a writer for the College of Veterinary Medicine.
