Drug-resistant tuberculosis (DR-TB) remains a major public health challenge in South Africa, particularly in rural settings with constrained access to rapid molecular diagnostics. There is a need to identify locally relevant molecular targets that could inform the future development of affordable point-of-care (POC) diagnostic platforms. This study used routine DR-TB surveillance data to develop an epidemiology-guided framework for prioritizing molecular targets for future molecular–biophotonic diagnostic development. A retrospective secondary analysis was conducted using routine DR-TB programme data from 402 patients managed at two decentralized treatment facilities in the rural Eastern Cape Province, South Africa, between 2020 and 2024. Resistance categories, treatment outcomes, and programme vulnerability indicators were analysed descriptively. A diagnostic prioritization framework integrating disease burden, frequency of resistance categories, treatment outcome vulnerability, programme impact, and potential suitability for decentralized implementation was used to prioritize established resistance-associated molecular targets. Molecular targets were informed by published evidence; no isolate-level mutation analysis, sequencing, biosensor development, or analytical or clinical validation of a diagnostic platform was performed. Rifampicin-resistant tuberculosis (RR-TB) (47.5%) and multidrug-resistant tuberculosis (MDR-TB) (44.3%) accounted for 91.8% of DR-TB cases, while pre-extensively drug-resistant tuberculosis (pre-XDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) accounted for 5.7% and 2.5%, respectively. Declining treatment success and increasing proportions of unevaluated outcomes among RR-TB and MDR-TB indicated programme vulnerability; however, the available data did not permit causal attribution of these patterns to diagnostic limitations. The framework prioritized rpoB, katG, and inhA as high-priority targets, followed by gyrA, gyrB, rrs, and eis as medium-priority targets, with embB, pncA, Rv0678, atpE, and pepQ identified for future expansion. These targets were conceptually mapped to candidate biophotonic biosensing approaches; their diagnostic performance and POC suitability were not evaluated in this study. This study proposes an epidemiology-guided framework for prioritizing molecular targets for future DR-TB diagnostic development in rural settings. The molecular–biophotonic component is conceptual and does not represent a validated diagnostic technology. Mutation-level characterization, biosensor development, analytical evaluation, and prospective clinical validation are required to determine the performance, feasibility, and potential POC applicability of the proposed approach.
Hussein Salad Yusuf, Abdirisak Ali Abukar, Mohamed Said Adan, Abdiaziz Siad Mohamed, Zakariye Yusuf Mohamed, Mustaf Abdi Ulusow, Mohamed Osman Dahir Alasow, Abdiwahid Ahmed Ibrahim, Naimo Awil Dahir
Spondylodiscitis is an important cause of spinal morbidity in tuberculosis (TB)-endemic settings, where limited microbiological capacity may complicate differentiation of tuberculous from non-tuberculous disease. Data describing the clinical spectrum and outcomes of spondylodiscitis in Somalia are limited. To describe the demographic, clinical, radiological, microbiological, treatment, and outcome characteristics of patients with spondylodiscitis and to explore factors associated with clinical outcome. We conducted a retrospective observational study of 121 eligible patients diagnosed with spinal infection at Mogadishu Somali Turkey Recep Tayyip Erdoğan Training and Research Hospital between 1 August 2023 and 31 July 2024. Demographic, clinical, radiological, microbiological, treatment, and outcome data were extracted from routine records. Associations were assessed using chi-square or Fisher's exact tests for categorical variables and Mann–Whitney U or independent-samples t-tests as appropriate for continuous variables. Outcome comparisons were restricted to patients with documented follow-up; multivariable logistic regression was not retained because only 19 unfavorable outcomes were available and outcome ascertainment was incomplete. The mean age was 48.8 ± 18.1 years and 53.7% were male. Back pain (92.6%) and radicular pain (82.6%) were the most frequent presenting symptoms. Neurological deficit was documented in 46.3% and spinal deformity in 38.0%. Lumbar involvement was most common (48.8%), followed by thoracic involvement (25.6%); anterior-column involvement occurred in 97.5%. Epidural abscess was identified in 69.4% and is reported here as a radiological finding. Microbiological or histopathological testing was performed in 46 patients; 30 were TB-positive, corresponding to 65.2% positivity among tested patients and 24.8% confirmed TB among the total cohort. Eighty-five patients (70.2%) received empirical anti-TB treatment. Among 65 patients with documented follow-up, 46 (70.8%) achieved favorable outcomes. In bivariate analysis, TB exposure history was associated with outcome (p = 0.003), whereas operative/procedural intervention was not significantly associated with outcome (Fisher's exact p = 0.399). Spondylodiscitis in this Somali tertiary-care cohort showed a substantial burden of neurological and radiological complications and a high proportion of empiric TB treatment. Because microbiological confirmation was limited and follow-up was incomplete, the observed confirmed TB proportion and favorable-outcome estimate should not be interpreted as population-level estimates. Prospective multicenter studies with systematic microbiological testing and complete follow-up are needed to clarify the etiological spectrum and prognostic factors.
Tuberculosis (TB) remains a major global health challenge, with undernutrition recognized as one of the most significant modifiable risk factors influencing disease susceptibility and clinical outcomes. Emerging evidence suggests that nutritional status may also affect TB risk indirectly through its impact on thyroid function and immune regulation. This review examines the current evidence linking nutrition, thyroid dysfunction, and susceptibility to Mycobacterium tuberculosis (M. tuberculosis), with particular emphasis on the biological mechanisms that connect these factors. Essential micronutrients, including iodine, selenium, iron, zinc, and vitamin D, are critical for thyroid hormone synthesis, metabolism, antioxidant defense, and immune function. Deficiencies in these nutrients can impair thyroid physiology, disrupt endocrine homeostasis, and alter innate and adaptive immune responses that are essential for controlling M. tuberculosis infection. Thyroid hormones regulate macrophage activation, T-cell differentiation, cytokine production, immunometabolism, and oxidative stress, suggesting that thyroid dysfunction may compromise host resistance to TB. Conversely, chronic TB infection and antitubercular therapy may further disrupt thyroid function, creating a bidirectional relationship between these conditions. Collectively, the available evidence supports a conceptual framework in which nutritional deficiencies contribute to thyroid dysfunction, thyroid dysfunction impairs antimicrobial immunity, and TB further exacerbates nutritional and endocrine disturbances, establishing a self-perpetuating cycle that may increase disease susceptibility and worsen clinical outcomes. Although direct clinical evidence linking thyroid disorders with TB risk remains limited, the convergence of nutritional, endocrine, and immunological pathways provides a strong biological rationale for further investigation. Future prospective studies are needed to determine whether nutritional optimization, targeted micronutrient supplementation, and early identification and management of thyroid dysfunction can improve immune competence, reduce TB susceptibility, and enhance treatment outcomes in high-risk populations.
Glory M. Velazquez, Jonathan Z. Sexton, Scott G. Franzblau, Gauri S. Shetye, Akil Hossain, George A. Garcia
In 2023, tuberculosis (TB) once again became the world's deadliest infectious disease, overtaking COVID-19 as the leading cause of death from a single infectious agent, Mycobacterium tuberculosis (MTB). The World Health Organization (WHO) reports that the COVID-19 pandemic has reversed years of progress in providing essential TB services and reducing TB disease burden. In 2025, TB was responsible for an estimated 1.23 million deaths globally (95% uncertainty interval: 1.13–1.33 million), and there were 400 K cases of rifamycin resistant/multidrug resistant TB (RR, RIFR, MDR). While treatment success for drug susceptible TB remains high (88%), outcomes for MDR/RR-TB are lower but improving, reaching 71% globally. Clearly, there is a critical unmet need for novel antibiotics against MTB, exacerbated now due to COVID-19. The limited success in pursuing novel targets underscores the urgent need to revisit and reevaluate the mechanisms of action behind existing and once effective drugs, a strategy that may hold untapped potential in the fight against growing antibiotic-resistant TB. The MTB RNA polymerase (RNAP) is a proven target for TB treatment by rifampin (RMP), which kills both active and latent MTB. However, RMP suffers from several drawbacks including: long treatment times, activation of hPXR (inducing Cyp3A4 which is problematic for HIV-TB coinfection), and resistant mutations within RNAP. Two newer treatments with novel mechanisms of action include bedaquiline and delamanid, the former has been approved by the FDA for the treatment of multiple-drug resistant tuberculosis (MDR-MTB); however, even these new drugs already have incidences of acquired resistance. Our goal is to develop novel drug candidates for TB treatment that: target RNAP, have the potential to shorten treatment times, and have activity against RIF R mutants. Our approach, orthogonal to the rifamycins, is to target the interaction of MTB RNAP with the required transcription factor CarD. We have previously labeled CarD with the BODIPY-FL fluorophore via engineered cysteine mutations and developed a fluorescence polarization assay to monitor its interaction with RNAP and promoter DNA. Leveraging this target, we screened a 24 K small molecule library against CarD binding to MTB RNAP. We have now extended this screening to∼88,000 additional molecules.
Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis secretes proteins during the host-pathogen interaction that facilitate its survival and/or virulence within host cells. Key examples include EsxA and EsxB, CpnT/TNT, phosphatases (SapM, PtpA, PtpB), protein kinase G (PknG), the antigen 85 (ag85) complex, acyl Carrier Protein (AcpM), lipoproteins, and heat shock proteins (Hsps). Together, these secreted factors disrupt host immune responses such as phagosome maturation, antigen presentation, cytokine production, and autophagy thereby aiding in survival of these obligate intracellular bacteria. Several secreted proteins are emerging as therapeutic targets to help meet the need for shorter, more effective, and better tolerated treatment regimens for tuberculosis. Here, we review the current understanding of the major secreted proteins of M. tuberculosis. We also discuss progress in the discovery and development of drugs targeting these proteins. Overall, targeting M.tuberculosis secreted proteins remains largely in the preclinical stages of drug development. Current limitations include low potency, off-target activity, and redundancy among secreted proteins.
