Mycobacterial Infection: Pathogenesis and Drug Development

A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Bacterial Pathogens".

Deadline for manuscript submissions: closed (15 December 2025) | Viewed by 3888

Special Issue Editor


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Guest Editor
Department of Biological Sciences, Virginia Tech, Blacksburg, VA 2406, USA
Interests: mycobacteria in household plumbing; biofilm formation by mycobacteria; mycobacterial gene transfer; identification of new anti-mycobacterial antibiotics
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Special Issue Information

Dear Colleagues,

The breadth of topics in this Special Issue of Pathogens might seem rather wide; however, individuals consider that the topics are intertwined as the mycobacteria are intracellular pathogens. Further, the progress of studies of mycobacterial pathogenesis and drug delivery needs to be accelerated by novel concepts concerning these two topics. Thus, there is strong justification for this Special Issue.

To contribute to the need for novel concepts concerning mycobacterial pathogenesis and drug development, the Editor offers the following hypothesis. Although the mycobacteria grow slowly, they have a robust metabolism. Slow growth is due, in part, to the diversion of resources (namely ATP) to the synthesis of long-chain fatty acids (C60-C80) for the almost drug-impregnable outer membrane. Slow death is characteristic of the mycobacteria, but with rapid metabolism, there is energy to adapt to the challenges of survival in phagocytic cells and the imbalances due to antibiotic exposure before cells are killed. Adaptations could permit the survival of phagocytozed or drug-exposed mycobacterial cells. What about looking for novel proteins or mRNAs in such mycobacterial cells?

Prof. Dr. Joseph Oliver Falkinham
Guest Editor

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Keywords

  • mycobacteria
  • adaptation
  • phagocytic survival
  • drug-exposed recovery
  • resource diversion
  • dormancy
  • persisting cells

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Published Papers (4 papers)

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Research

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14 pages, 1275 KB  
Article
Association of Antimicrobial Susceptibility with Treatment Response in Mycobacterium avium complex Pulmonary Disease
by Xuejiao Luo, Yuhang Chen, Lina Davies Forsman, Yifan He, Guoling Yang, Wei Wei, Hai Lou, Li Wang, Lan Yao, Yidian Liu, Judith Bruchfeld, Jan-Willem Alffenaar, Biao Xu, Xubin Zheng and Wei Sha
Pathogens 2025, 14(12), 1218; https://doi.org/10.3390/pathogens14121218 - 29 Nov 2025
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Abstract
Understanding the clinical implications of minimum inhibitory concentration (MIC) may facilitate optimal drug selection in Mycobacterium avium complex pulmonary disease (MAC-PD) treatment. This study aimed to investigate the association of individual MICs with treatment response of MAC-PD. A retrospective cohort study was conducted [...] Read more.
Understanding the clinical implications of minimum inhibitory concentration (MIC) may facilitate optimal drug selection in Mycobacterium avium complex pulmonary disease (MAC-PD) treatment. This study aimed to investigate the association of individual MICs with treatment response of MAC-PD. A retrospective cohort study was conducted in China, including eligible patients diagnosed with MAC-PD between 2018 and 2021. Treatment success rates were calculated across different MIC levels in a subgroup of patients receiving relatively uniform regimens. Associations between MICs and treatment outcomes were investigated by logistic regression analysis. In total, 209 patients with confirmed MAC-PD and initiated treatment were included. The median age was 60.0 years. Among 155 patients who completed treatment, 67.1% achieved treatment success. The treatment success rate was low in patients with clarithromycin MIC ≥ 64 mg/L (25.0%, 1/4) or ethambutol MIC > 16 mg/L (42.9%, 3/7), while remaining relatively stable (75–100%) at other MIC levels. Univariate analyses showed that clarithromycin and ethambutol MICs above these thresholds were associated with increased risk of treatment failure. Our findings suggest an association between clarithromycin MICs and treatment outcomes in patients with MAC-PD receiving standard guideline-recommended regimens. Meanwhile, elevated ethambutol MICs exhibited potential clinical relevance, warranting further investigation. Full article
(This article belongs to the Special Issue Mycobacterial Infection: Pathogenesis and Drug Development)
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16 pages, 876 KB  
Article
M72 Fusion Proteins in Nanocapsules Enhance BCG Efficacy Against Bovine Tuberculosis in a Mouse Model
by Federico Carlos Blanco, Renée Onnainty, María Rocío Marini, Laura Inés Klepp, Elizabeth Andrea García, Cristina Lourdes Vazquez, Ana Canal, Gladys Granero and Fabiana Bigi
Pathogens 2025, 14(6), 592; https://doi.org/10.3390/pathogens14060592 - 16 Jun 2025
Cited by 2 | Viewed by 1356
Abstract
Mycobacterium bovis is the causative pathogen of bovine tuberculosis (bTB), a disease that affects cattle and other mammals, including humans. Currently, there is no efficient vaccine against bTB, underscoring the need for novel immunization strategies. The M72 fusion protein, composed of three polypeptides derived [...] Read more.
Mycobacterium bovis is the causative pathogen of bovine tuberculosis (bTB), a disease that affects cattle and other mammals, including humans. Currently, there is no efficient vaccine against bTB, underscoring the need for novel immunization strategies. The M72 fusion protein, composed of three polypeptides derived from Mycobacterium tuberculosis and M. bovis, has demonstrated protective efficacy against M. tuberculosis in clinical trials when combined with the AS01E adjuvant. Given the established efficacy of nanocapsule formulations as vaccine delivery systems, this study evaluated a novel immunization strategy combining BCG with either full-length M72 or a truncated M72 fused to a streptococcal albumin-binding domain (ABDsM72). Both antigens were encapsulated in chitosan/alginate nanocapsules and assessed in a murine M. bovis challenge model. Priming with BCG followed by an M72 boost significantly improved splenic protection compared to BCG alone, but it did not enhance pulmonary protection. Notably, boosting with ABDsM72 further increased the proportion of CD4+KLRG1-CXCR3+ T cells in the lungs of M. bovis-challenged mice, a key correlate of protective immunity. These findings demonstrate that chitosan/alginate-encapsulated antigens enhance BCG-induced immunity, supporting their potential as next-generation vaccine candidates for bTB control. Full article
(This article belongs to the Special Issue Mycobacterial Infection: Pathogenesis and Drug Development)
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Review

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25 pages, 360 KB  
Review
Detection, Isolation, and Identification of Mycobacteria That Cause Nontuberculous Mycobacterial Disease and Tuberculosis
by Lyudmila Severova, Dmitrii Giller, Inga Enilenis, Patimat Gadzhieva, Galina Shcherbakova, Oleg Kesaev, Vadim Koroev, Olga Frolova, Anna Popova, Alexandr Ilyukhin, Valeria Basangova, Elena Belova, Elham Pahlevani Gazi, Irina Taushkanova and Ivan Martel
Pathogens 2025, 14(12), 1302; https://doi.org/10.3390/pathogens14121302 - 18 Dec 2025
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Abstract
Pulmonary diseases caused by nontuberculous mycobacteria are increasingly becoming common worldwide and are occurring more frequently alongside pulmonary tuberculosis. Given that pulmonary diseases resulting from nontuberculous mycobacteria and pulmonary tuberculosis display similar features—such as clinical manifestations, imaging findings, and laboratory results—the accurate differentiation [...] Read more.
Pulmonary diseases caused by nontuberculous mycobacteria are increasingly becoming common worldwide and are occurring more frequently alongside pulmonary tuberculosis. Given that pulmonary diseases resulting from nontuberculous mycobacteria and pulmonary tuberculosis display similar features—such as clinical manifestations, imaging findings, and laboratory results—the accurate differentiation of each disease type is highly challenging. Mycobacterial culture, as a gold standard method, cannot be considered completely trustworthy because of low bacterioexcretion rates among nontuberculous mycobacterial pulmonary patients. Additional problems result from poor diagnosis. The treatment of lung diseases caused by nontuberculous mycobacteria is also difficult. This could be due to the wide spectrum of bacteria belonging to nontuberculous mycobacteria, as well as low bacterioexcretion. Therefore, bacterial sensitivity to drugs is insufficient. As a result, in this article, our intention is to explain the diagnostic difficulties of pulmonary diseases caused by nontuberculous mycobacteria and the Mycobacterium tuberculosis complex. The review seeks to outline promising directions for the development of novel diagnostic approaches in order to improve clinical decision-making and ultimately treatment outcomes. Full article
(This article belongs to the Special Issue Mycobacterial Infection: Pathogenesis and Drug Development)

Other

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9 pages, 1038 KB  
Opinion
Proposing Bromo-Epi-Androsterone for Host-Directed Therapy Against Tuberculosis
by Coad Thomas Dow and Liam Obaid
Pathogens 2025, 14(11), 1179; https://doi.org/10.3390/pathogens14111179 - 18 Nov 2025
Viewed by 560
Abstract
Bromoepiandrosterone (BEA), a synthetic analog of the adrenal steroid DHEA, holds promise as a host-directed therapy for both active and latent tuberculosis (TB). Unlike DHEA, BEA lacks hormonal side effects yet retains potent immunomodulatory activity. It promotes a Th1-skewed immune response by enhancing [...] Read more.
Bromoepiandrosterone (BEA), a synthetic analog of the adrenal steroid DHEA, holds promise as a host-directed therapy for both active and latent tuberculosis (TB). Unlike DHEA, BEA lacks hormonal side effects yet retains potent immunomodulatory activity. It promotes a Th1-skewed immune response by enhancing interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), critical cytokines for macrophage activation and intracellular control of Mycobacterium tuberculosis (Mtb), while suppressing Th2 cytokines such as IL-4. BEA also inhibits 11β-hydroxysteroid dehydrogenase-1, lowering intracellular cortisol levels and reversing the local immunosuppression commonly seen in TB. These features enable BEA to restore immune competency in TB-infected tissues. In murine TB models, BEA halted bacterial growth, reduced pulmonary inflammation, and synergized with standard anti-TB drugs to enhance bacterial clearance. Additionally, DHEA and its analogues have demonstrated direct antimycobacterial activity, likely by interfering with Mtb mycolic acid synthesis, a property BEA is believed to share. For latent TB, BEA’s ability to sustain Th1-mediated immunity and counteract immune suppression could help maintain latency and prevent reactivation, especially in immunocompromised individuals. By boosting immune surveillance and potentially contributing to bacillary clearance, BEA offers a unique adjunctive approach that complements existing TB treatments without contributing to drug resistance. Its dual function, an immune modulator and antimicrobial agent, supports its use across the TB disease spectrum. These properties position BEA as a novel candidate for host-directed therapy aimed at improving outcomes in both drug-sensitive and drug-resistant TB, as well as therapies aimed at enhancing long-term containment of latent infection. Full article
(This article belongs to the Special Issue Mycobacterial Infection: Pathogenesis and Drug Development)
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