Host-Directed Therapy and Drug Repurposing in Tuberculosis: A Scoping Review of Emerging Adjunctive Strategies

Tuberculosis (TB) remains one of the leading infectious causes of death worldwide, with millions of new cases reported annually. The emergence and spread of drug-resistant tuberculosis (DR-TB), including multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB), has significantly complicated global TB control efforts. Current treatment regimens for DR-TB are prolonged, toxic, and costly, with suboptimal treatment success rates. Resistance in Mycobacterium tuberculosis largely occurs through chromosomal mutations affecting targets of anti-tuberculosis drugs. Although new drugs such as bedaquiline and delamanid have been introduced, resistance to these agents has already begun to emerge. Therefore, innovative strategies that complement conventional antimicrobial therapy are urgently required. Host-directed therapy (HDT) has emerged as a promising approach in infectious disease management. Unlike conventional antibiotics that target the pathogen directly, HDT aims to enhance host immune responses, restore immune homeostasis, and limit pathological inflammation. By targeting host pathways, HDT may reduce selective pressure on the pathogen and potentially limit the emergence of drug resistance. Drug repurposing represents another practical strategy for accelerating TB treatment innovation. Repurposed drugs have known safety profiles, established pharmacokinetics, and existing manufacturing infrastructure, allowing faster translation into clinical practice. Various repurposed agents—including antibiotics, metabolic modulators, anti-inflammatory drugs, antidepressants, and lipid-modifying agents—have shown promising immunomodulatory or antimycobacterial effects in preclinical and clinical studies. Despite growing research on HDT and drug repurposing in TB, the evidence remains scattered across experimental studies, animal models, and clinical trials. A comprehensive mapping of this evidence is necessary to identify promising candidates, understand their mechanisms of action, and determine existing knowledge gaps. This scoping review aims to systematically map the current evidence on repurposed drugs and host-directed therapies used as adjunctive treatments for tuberculosis, with particular emphasis on their potential role in preventing or limiting the development of drug resistance.