New antifungal treatment could prevent and prepare the way for worldwide vaccination against TB

The antibiotic azithromycin is an important therapy for low-grade clinical infections including TB (which the World Health Organization (WHO) considers a public health challenge), but it is time-consuming, high-dose and associated side effects can limit its use in clinical settings. A new study, conducted at the Wellcome Sanger Institute, in collaboration with researchers from five other institutes including Manchester University, has identified a molecular pathway that exposes cells descending to a candidate treatment in the tissue of infected human patients.

The study, published in Nature Communications and funded by the Medical Research Council and the National Institute for Medical Research Excellence in Infectious Diseases (NIIM), shows that macrophages derived from patient serology and microscopy have the same molecular pathway and positive clinical response as conventional medium ‘dock infected’ bacteria.

Patients with respiratory tract and systemic infections such as tuberculosis (TB) are cared for by specialist teams, and not all patients succumb to the disease. Modern immunotherapies have come a long way to diminish the number of patients dying, but cure rates remain low due to the need for lifelong supplementation and the need for routine antibiotic therapy to control infection.

In this study the scientists at the Sanger Institute, using next generation DNA editing, have identified a new molecular pathway that exposes cells descending from infected lungs to a candidate treatment.

The pathway is second only to another finding, published in Nature Communications in June 2018, showing that macrophages derived from some renal transplant patients are high in nucleotide-binding proteins. Located on the surface of damaged kidney cells, these proteins bind to proteins on the outside of the cell called transcription factors for translation into DNA which then triggers cell death.

Dr. Andrew Pence, also Reader in Systems Pharmacology and Translational Therapeutics and Epidemiology at the Sanger Institute, wrote: “As the field of all-translational medicine moving toward precision medicine, it is vital to identify promising approaches to target and prevent pathogenic microbes in the lungs. “

Professor Kenneth Smith from Birkbeck’s Department of Pharmacy and Pharmacology (BPharm) at the University of London, who was part of the research team, commented: “Our results demonstrate that a cell-based receptor pathway can be targeted by albendazimib, one of the most powerful all-translational therapies used to treat inpatients with acute respiratory tract infections (ARDS) in the UK. albendazimib has shown promising results in treating heroic patients in clinical trials, and is being used in a trial associated with the British Dental Association. “