Cholera remains a major health concern worldwide, particularly among children, as the disease has become increasingly resistant to antibiotics in recent years. According to Illinois Tech Associate Professor of Biology Oscar Juarez, “In a recent study in sub-Saharan Africa and many other places cholera is prevalent, it is shown that 100 percent of the clinical samples they have are resistant to multiple antibiotics.” He also noted the significant impact of cholera outbreaks, such as the one in Haiti that overwhelmed the country's healthcare system.
A research team at Illinois Institute of Technology led by Juarez—including Ph.D. students Ming Yuan and Yuyao Hu, postdoctoral researcher Martin Andres Gonzalez Montalvo, and Assistant Professor Karina Tuz—has identified a new approach to address this challenge. The group repurposed clofazimine, an orphan drug previously used for leprosy and tuberculosis but discontinued in the United States nearly ten years ago, showing its effectiveness against multi drug-resistant strains of cholera.
The team focused on how Vibrio cholerae survives in humans by targeting a protein called NQR that is crucial for the bacteria’s energy production. Juarez explained: “Our study shows that NQR is super important for Vibrio cholerae to produce energy. We identified where exactly it is that clofazimine binds to,” adding: “The cell has thousands of different proteins. What we did was identify the target of clofazimine in Vibrio cholerae, which is NQR.”
Instead of screening thousands of molecules typically required in drug discovery, Juarez’s group narrowed their search due to prior knowledge about inhibitory properties needed for NQR. “What we’re doing is actually engineering drug design, because we know the properties of molecules that should have inhibitory effects over NQR and over Vibrio cholerae,” said Juarez. “We have enough information to be able to predict the type of molecules that have inhibitory properties and to speed up drug discovery and drug design.”
The next phase involves modifying clofazimine by adjusting its chemical structure to enhance its effectiveness against cholera—a process Juarez likens to playing Tetris with molecular structures. “When you’re playing Tetris, you’re making something fit in a specific position,” he said. “What we’re doing is taking the structure of clofazimine—which fits well into the pocket of a protein—and if we include another chemical group that makes it fit better, then it will be more potent.”
An advantage of using an existing FDA-approved drug like clofazimine is bypassing much of the lengthy and costly approval process required for new drugs. As Juarez stated: “The approval requires about $2.1 billion and about 10 years of testing. The three levels of clinical trials in humans, we may skip them, because we already know clofazimine is safe.”
Juarez estimates this could lead to an affordable treatment option for multi drug-resistant cholera at around $20 per dose. The team is currently seeking a patent for this use.