Basel: Experts are developing revolutionary immune-boosting drugs known as host-directed therapythose who employ the body immune system To target TB, while also tackling drug-resistant forms of the disease.

Susanna Brighenti, Associate Professor, ANA Futura, Center for Infectious Medicine (CIM), ANA Futura, at Karolinska Institutet, Stockholm, Sweden, will give a presentation at this year’s ESCMiD Global Congress (formerly ECCMID) in Barcelona.

The global number of new people diagnosed with TB in 2022 is projected to be 7.5 million, leading to an estimated 1.3 million deaths. An estimated 410,000 cases and 160,000 deaths were caused by multidrug-resistant TB (MDR-TB).

“Mycobacterium tuberculosis (Mtb) has evolved a remarkable ability to manipulate the human immune response and attenuate antimicrobial effector functions in host immune cells,” explains Associate Professor Brighenti.

“Although some new antimicrobial treatments are emerging, treatment with antibiotics remains an intensive and lengthy process even for drug-susceptible forms of the disease. Importantly, mutations provide antibiotic resistance Mycobacteria have intrinsic properties that effectively develop resistance to old and new groups of antibiotics, increasing the need for adjuvant treatment. Thus, new treatments will be absolutely vital in the fight against TB.”

Host-directed therapy (HDT) aims to strengthen the body’s immune responses and represents an unexplored opportunity to improve the treatment of TB, especially MDR-TB. HDTs are designed to target multiple immune pathways in infected cells to restore or induce antimicrobial functions rather than directly inhibit bacterial growth.

This may include increased production of immune peptides or toxic molecules that contribute to killing bacteria, but it may also involve rebalancing of inflammatory responses. Associate Professor Brighenti will explain how their research collaboration has created a platform for immune reconstitution in TB using small molecule compounds, including histone deacetylase (HDAC) inhibitors.

“These drugs can regulate the transcription of genes in immune system-like cells, and thus increase the expression of proteins associated with antibacterial host defense. We have identified several HDAC inhibitors that virtually suppress Mtb growth inside immune cells. By 50-75 percent, even in the absence of antibiotics,” she explains.

“It may not seem that impressive, but these immunomodulatory compounds can work well as supplements to standard therapy and can have additive or synergistic effects when combined with antibiotics. With the possibility of reducing the required dose and duration of treatment.

Thus, it is conceivable that the effects of existing antibiotics could be preserved by add-on therapy that restores protective immunity and limits additional inflammation and/or immunosuppression in TB patients. Standard anti-TB treatment involves daily administration of 4–9 antibiotics, but instead of adding another antimicrobial drug to the regimen, an immune-boosting compound may be used to treat severe forms of TB and poor prognosis, especially MDR-TB. May promote clinical recovery of patients with. ,

Associate Professor Brighenti says, “Implementation immunotherapy As a complement to standard therapy it has revolutionized the treatment of cancer, autoimmunity and asthma/allergies. Similarly, our research on immune enhancement as a complement to antibiotics could become a game-changing treatment option for TB patients that has the potential to make an impact. clinical management And stop the spread of TB infection and drug resistance at this critical moment in our history antimicrobial resistance This is a serious threat to human health.”

She adds, “Short-term, approved and already available ‘off-the-shelf’ therapeutics would represent an initial logical step towards implementing HDT of TB patients. This could include, for example, glucocorticoid treatment or cytokine HDTs based on neutralization (for example, anti-IL-6, anti-1B) may be included to reduce inflammation, while metformin, or non-steroidal anti-inflammatory drugs may also boost the immune response. Or you can activate it again.

“Long-term, more precise immunomodulatory interventions in TB such as local administration of specific HDAC inhibitors can be tested in clinical trials aimed at optimizing therapy for patients with MDR-TB. Today, several HDAC inhibitors are FDA-approved for various diseases – for example, vorinostat, belinostat, and panobinostat for various cancers, phenylbutyrate for urea cycle disorders, and givinostat for Duchenne muscular dystrophy, while those we have developed for reducing intracellular M. tuberculosis growth have been found to be most effective, they first need to be tested in pre-clinical models for toxicity and efficacy before moving forward into clinical trials.”

Importantly, like many other diseases, TB can be divided into different sub-groups and it is not necessary to use a one-size-fits-all approach to treatment. Tailored treatment to the needs of the individual patient, called personalized medicine, will also be part of the future for TB management.