Novel strategies against drug-resistant tuberculosis: a comprehensive review from molecular mechanisms to clinical translation
Abstract
In 2023, an estimated 13% of worldwide deaths resulting from antimicrobial resistance (AMR) were due to drug-resistant TB (DR-TB). The World Health Organization (WHO) documented a dramatic, sixfold increase in the number of patients treated with 6-month all-oral (BPaLM) regimens, from 5,653 patients in 2023, to 34,000 patients by 2024, while also documenting an emergence of bedaquiline resistance in real-world cohorts and a lack of efficacy of BCG revaccination in the BCG-PRIME Phase 2b trial against sustained Mycobacterium tuberculosis infection. Concurrently, the M72/AS01E subunit vaccine trial completed recruitment (approximately 20,000 individuals) across five high-burden countries, 11 months ahead of scheduled completion date. The first randomized controlled trial assessing DRTB-HDT host-directed therapy for DR-TB in adults (metformin + dovramilast), conducted at five international sites, is entering the late-stage readout phase. This synthesis of data, covering the period from 2015 through 2026, across six different dimensions includes molecular mechanisms of resistance, novel antimicrobial treatment modalities, host-directed therapy, immunity associated with regulatory compliance, adjuvants to vaccines, and the clinical translation of vaccine candidates. The Molecular-to-Translational continuum is used as a framework for the synthesis, with the regulatory immune function domain (T regulatory cells, myeloid-derived suppressor cells, and check-point axes) linking all five domains. Our central hypothesis is that drug resistance evolution of the microbe and failure of the host to maintain regulatory immunity are interdependent and create a bidirectional relationship with each other. We have identified nine major research gaps, with milestone dates from 2026 to 2030, based on unresolved controversies regarding the bedaquiline resistance catalog and the acquisition versus transmission narrative.