Researchers at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine), have demonstrated that doxycycline, a commonly available and inexpensive antibiotic, can improve survival rates and neurological outcomes in Central Nervous System Tuberculosis (CNS-TB) in a preclinical non-human study. Published in the Journal of Neuroinflammation, the study offers a promising adjunctive therapy for this severe and often fatal disease.
The study, led by Associate Professor Catherine Ong Wei Min, Principal Investigator from the Infectious Diseases Translational Research Programme at NUS Medicine, together with co- lead authors Dr Poh Xuan Ying and Dr Loh Fei Kean, who are from the same programme, studied the prognostic factors of CNS-TB. They analysed cerebrospinal fluid samples collected from 72 children with tuberculous meningitis and control patients and found elevated levels of tissue- damaging matrix metalloproteinases (MMPs) proteins and immune cell traps known as neutrophil extracellular traps (NETs), which drives the severity of CNS-TB, in the cerebrospinal fluid of children with CNS-TB.
While TB is generally associated with pulmonary TB which affects the lungs, CNS-TB is a more severe form of TB that affects the brain and spinal cords and occurs more commonly among children and the immunocompromised.
To investigate targeted treatment, the researchers developed a CNS-TB laboratory model that exhibited the brain pathology and neurological symptoms similar to those observed in humans, and contained TB bacteria. An RNA sequencing platform optimised for old and small archived tissue was used to analyse gene expression changes from TB infections in human and research tissue samples.
Their research found that treating the CNS-TB laboratory models with doxycycline alongside standard TB drugs suppressed MMPs and NETs, significantly improved survival and outcomes. The addition of doxycycline lowered inflammation, preserved brain tissue, and improved vascular integrity, leading to better drug penetration and outcomes.
Assoc Prof Ong said, "Our study suggests that doxycycline, when paired with standard TB drugs, curbs excessive immune activity that leads to brain damage and improve survival rates in preclinical studies. Doxycycline is inexpensive, widely available and has a well-established safety record. If these findings are confirmed in Phase II studies, its use could eventually be rapidly scaled across national TB programmes without the long delays typical of new drug development."
Collaborators of the study include Assistant Professor Joshua Tay from the Department of Otolaryngology, NUS Medicine; Associate Professor Andres F. Vallejo from the University of Southampton, UK; and Professor Tchoyoson Choie Cheio Lim from the Department of Neuroradiology at the National Neuroscience Institute, Singapore.
TB is a global health threat with more than 10.8 million cases of active TB recorded in 20231. Singapore continues to see endemic transmission, with about 1,100 new active cases in 20241. CNS-TB represents about 1 to 2 per cent of all global TB cases, with patients continuing to face neurological damage and high mortality despite receiving standard TB treatment2. This work underscores the potential of repurposing an inexpensive, well-tolerated drug such as doxycycline to improve treatment of CNS-TB and possibly other inflammatory brain infections. The study results have led to a Phase II clinical trial funded by the National Medical Research Council (NMRC) at the Ministry of Health, Singapore, that is currently ongoing in Singapore, Malaysia and Indonesia, to assess if adding doxycycline to standard TB treatment can safely improve survival and reduce brain damage in patients.
"As our study proceeds to the next phase, we aim to create a robust clinical dataset that enables us to develop more targeted and effective TB treatment, ultimately offering patients a better chance at a fuller recovery," said Assoc Prof Ong.
