Rutgers Health researchers have made a significant breakthrough in understanding why bedaquiline, a relatively new antibiotic, is effective against multidrug-resistant strains of tuberculosis (TB). The study, published in Nature Communications, reveals that deficiencies in a critical enzyme, catalase-peroxidase, make drug-resistant TB bacteria more susceptible to bedaquiline. This discovery could pave the way for improved treatments and drug development strategies.
Understanding Bedaquiline's Mechanism
Approved by the FDA in 2012, bedaquiline was the first new TB drug in over 40 years. While its effectiveness against multidrug-resistant TB strains was known, the underlying mechanisms were not fully understood. The Rutgers study sheds light on this, revealing that mutations in the katG gene, which encodes the catalase-peroxidase enzyme, are a key factor.
"Understanding how a drug works could help us design new molecules that work better and prevent bacteria from becoming resistant," said Jason Yang, assistant professor at Rutgers New Jersey Medical School and senior author of the study.
Catalase Deficiency and Drug Resistance
The researchers found that deficiencies in catalase-peroxidase lead to increased accumulation of reactive oxygen species and heightened susceptibility to DNA damage in drug-resistant TB strains. This catalase deficiency alters transcriptional programs and represses biosynthetic pathways, making the bacteria more vulnerable to bedaquiline.
"We discovered some previously unreported mechanisms," Yang said. "We show that these are the different kinds of vulnerabilities in TB biology or TB physiology that occur specifically in drug-resistant TB."
Potential for Drug Repurposing and Combination Therapies
The research also highlights the potential for repurposing existing drugs. The study found that trimethoprim and sulfamethoxazole, antibiotics used for other diseases, were also effective against drug-resistant TB strains with catalase deficiency. Furthermore, combining bedaquiline with isoniazid, another antibiotic, appeared to prevent the development of resistance to either drug.
Global Impact and Future Research
Tuberculosis remains a major global health threat, with over 1.5 million deaths annually. Multidrug-resistant TB poses a significant challenge to global TB control efforts. The findings from this study could inspire strategies for making bedaquiline more effective, potentially allowing for lower doses or shorter treatment times. Yang and his colleagues are also developing machine-learning tools to understand other changes occurring in TB biology due to drug resistance, with the goal of personalizing TB treatments based on the specific characteristics of the infecting strain.
"TB itself is a ridiculously important problem right now, and so is antibiotic resistance," Yang said. "There was just a new report in the Lancet projecting if antibiotic resistance becomes worse, then we can't treat infections, and if we can't treat infections, much of modern medicine dies."
