Breakthrough in TB Treatment: Immune-Boosting Drugs Show PromiseBreakthrough in TB Treatment: Immune-Boosting Drugs Show Promise

Researchers are working on novel immune-boosting medications called host-directed treatments, which use the body’s defenses against tuberculosis to attack drug-resistant versions of the disease. This year at the ESCMID Global Congress (previously ECCMID) in Barcelona, Associate Professor Susanna Brighenti of the Centre for Infectious Medicine (CIM), ANA Futura at the Karolinska Institutet, Stockholm, Sweden, will be presenting.

In 2022, there were 7.5 million newly diagnosed cases of tuberculosis worldwide, resulting in an expected 1.3 million fatalities from the disease. Multidrug-resistant tuberculosis was projected to be the cause of 410 000 infections and 160 000 deaths (MDR-TB). According to Associate Professor Brighenti, “Mycobacterium tuberculosis (Mtb) have evolved a remarkable ability to manipulate the human immune response and undermine antimicrobial effector functions in host immune cells.”

Even for illness forms that are amenable to drugs, administering antibiotics for therapy is still a rigorous and protracted procedure, notwithstanding the development of certain novel antimicrobial medicines. Crucially, mycobacteria possess inherent mutations that confer antibiotic resistance, which successfully acquire resistance to both novel and old antibiotic classes, underscoring the necessity of adjunct therapies. Therefore, developing novel treatments will be crucial in the fight against tuberculosis.

With the goal of enhancing the body’s immune responses, host-directed treatments (HDT) offer a little-known but promising way to treat tuberculosis, especially multidrug-resistant tuberculosis (MDR-TB). Rather of directly preventing bacterial growth, HDT are made to target many immunological pathways in infected cells in order to repair or induce antimicrobial capabilities. This could entail resetting inflammatory responses as well as increased synthesis of immune peptides or poisonous chemicals that aid in the death of bacteria.

Assoc Professor Brighenti will describe how her research team’s use of small molecule drugs, such as histone deacetylase (HDAC) inhibitors, has produced a platform for immunological reconstitution in tuberculosis. These medications have the ability to control gene transcription in immune system cells and other cells, which increases the expression of proteins linked to the host’s defense against germs. Even in the absence of antibiotics, we have discovered a number of HDAC inhibitors that suppress Mtb growth inside immune cells by approximately 50–75%,” she says. Although it may not sound very spectacular, these immunomodulatory substances have the potential to be a useful addition to conventional treatment, working in concert with antibiotics to produce synergistic or additive effects.

This would offer the opportunity to shorten the duration of treatment and lower the dose of antibiotics needed to enhance patient outcomes. Thus, it is plausible that adjuvant medicines that control excessive inflammation and/or immunosuppression in tuberculosis patients and restore protective immunity could mitigate the side effects of current medications. In place of adding yet another antibiotic to the standard anti-TB treatment regimen, an immune-enhancing substance could aid in the clinical recovery of patients with severe forms of tuberculosis and a dismal prognosis, particularly those with multidrug-resistant tuberculosis (MDR-TB).

“Immunotherapy as a complement to standard therapy has revolutionized the treatment of cancer, autoimmunity, and asthma/allergy,” adds Associate Professor Brighenti. Similar to this, at this critical juncture in history when antimicrobial resistance poses a serious threat to human health, our research on immune enhancement as an adjuvant to antibiotics may prove to be a game-changing therapeutic option for TB patients. It has the potential to impact clinical management and prevent the spread of TB infections and drug resistance. “Off-the-shelf” (or short-term, approved, and readily available) medications would represent an initial logical step to deploy HDTs of patients with tuberculosis,” the speaker continues.

To reduce inflammation, this could involve HDTs based on glucocorticoid therapy or cytokine neutralization (e.g., anti-IL-6, anti-1b). Non-steroidal anti-inflammatory medications (NSAIDs) or metformin may both enhance or rewire the immune response. “Clinical trials can test long-term, more precise immunomodulatory interventions in tuberculosis (TB), such as local administration of specific HDAC inhibitors, with the goal of tailoring therapy for MDR-TB patients.” The FDA has approved a number of HDAC inhibitors for various illnesses today, such as Givinostat for Duchenne muscular dystrophy, Phenylbutyrate for urea cycle disorders, and Vorinostat, Belinostat, and Panobinostat for various cancers.

However, the HDAC inhibitors that we have found to be most effective in reducing intracellular M. tuberculosis growth must first be tested for toxicity and efficacy in pre-clinical models before moving on to clinical trials. Crucially, there are various subgroups of tuberculosis, much like many other diseases, and treating all of them with the same treatment plan may not always be the best course of action. The future of tuberculosis management will also include personalised medicine—tailored medicines that are optimized to meet the needs of certain patients.

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