Tuberculosis (TB) remains a significant global health challenge, necessitating innovative approaches for effective treatment. Conventional TB therapy encounters several limitations, including extended treatment duration, drug resistance, patient noncompliance, poor bioavailability, and suboptimal targeting. Advanced drug delivery strategies have emerged as a promising approach to address these challenges. They have the potential to enhance therapeutic outcomes and improve TB patient compliance by providing benefits such as multiple drug encapsulation, sustained release, targeted delivery, reduced dosing frequency, and minimal side effects. This review examines the current landscape of drug delivery strategies for effective TB management, specifically highlighting lipid nanoparticles, polymer nanoparticles, inorganic nanoparticles, emulsion-based systems, carbon nanotubes, graphene, and hydrogels as promising approaches. Furthermore, emerging therapeutic strategies like targeted therapy, long-acting therapeutics, extrapulmonary therapy, phototherapy, and immunotherapy are emphasized. The review also discusses the future trajectory and challenges of developing drug delivery systems for TB. In conclusion, nanomedicine has made substantial progress in addressing the challenges posed by conventional TB drugs. Moreover, by harnessing the unique targeting abilities, extended duration of action, and specificity of advanced therapeutics, innovative solutions are offered that have the potential to revolutionize TB therapy, thereby enhancing treatment outcomes and patient compliance. 

Advanced drug delivery and therapeutic strategies for tuberculosis treatment

Infectious diseases, such as Mycobacterium tuberculosis (Mtb)-caused tuberculosis (TB), remain a global threat exacerbated by increasing drug resistance. Host-directed therapy (HDT) is a promising strategy for infection treatment through targeting host immunity. However, the limited understanding of the function and regulatory mechanism of host factors involved in immune defense against infections has impeded HDT development. Here, we identify the ubiquitin ligase (E3) TRIM27 (tripartite motif-containing 27) as a host protective factor against Mtb by enhancing host macroautophagy/autophagy flux in an E3 ligase activity-independent manner. Mechanistically, upon Mtb infection, nuclear-localized TRIM27 increases and functions as a transcription activator of TFEB (transcription factor EB). Specifically, TRIM27 binds to the TFEB promoter and the TFEB transcription factor CREB1 (cAMP responsive element binding protein 1), thus enhancing CREB1-TFEB promoter binding affinity and promoting CREB1 transcription activity toward TFEB, eventually inducing autophagy-related gene expression as well as autophagy flux activation to clear the pathogen. Furthermore, TFEB activator 1 can rescue TRIM27 deficiency-caused decreased autophagy-related gene transcription and attenuated autophagy flux, and accordingly suppressed the intracellular survival of Mtb in cell and mouse models. Taken together, our data reveal that TRIM27 is a host defense factor against Mtb, and the TRIM27-CREB1-TFEB axis is a potential HDT-based TB target that can enhance host autophagy flux.

TRIM27 elicits protective immunity against tuberculosis by activating TFEB-mediated autophagy flux.

De novo generation of molecules with the necessary features offers a promising opportunity for artificial intelligence, such as deep generative approaches. However, creating novel compounds having biological activities toward two distinct targets continues to be a very challenging task. In this study, we develop a unique computational framework for the de novo synthesis of bioactive compounds directed at two predetermined therapeutic targets. This framework is referred to as the dual-target ligand generative network. Our approach uses a stochastic policy to explore chemical spaces called a sequence-based simple molecular input line entry system (SMILES) generator. The steps in the high-level workflow would be to gather and prepare the training data for both targets' molecules, build a neural network model and train it to make molecules, create new molecules using generative AI, and then virtually screen the newly validated molecules against the SARS-CoV-2 PLpro and 3CLpro drug targets. Results shows that novel molecules generated have higher binding affinity with both targets than the conventional drug i.e. Remdesivir being used for the treatment of SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

De novo generation of dual-target ligands for the treatment of SARS-CoV-2 using deep learning, virtual screening, and molecular dynamic simulations.

The nonproton pumping type II NADH dehydrogenase in 

2-Aryl-Benzoimidazoles as Type II NADH Dehydrogenase Inhibitors of Mycobacterium tuberculosis

Drug-resistant tuberculosis (TB) outbreak has emerged as a global public health crisis. Therefore, new and innovative therapeutic options like host-directed therapies (HDTs) through novel modulators are urgently required to overcome the challenges associated with TB. In the present study, we have investigated the anti-mycobacterial effect of 4-(Benzyloxy)phenol. Cell-viability assay asserted that 50 μM of 4-(Benzyloxy)phenol was not cytotoxic to phorbol 12-myristate 13-acetate (PMA) differentiated THP-1 (dTHP-1) cells. It was observed that 4-(Benzyloxy)phenol activates p53 expression by hindering its association with KDM1A. Increased ROS, intracellular Ca2+ and phagosome-lysosome fusion, were also observed upon 4-(Benzyloxy)phenol treatment. 4-(Benzyloxy)phenol mediated killing of intracellular mycobacteria was abrogated in the presence of specific inhibitors of ROS, Ca2+ and phagosome-lysosome fusion like NAC, BAPTA-AM, and W7, respectively. We further demonstrate that 4-(Benzyloxy)phenol mediated enhanced ROS production is mediated by acetylation of p53. Blocking of p53 acetylation by Pifithrin-α (PFT- α) enhanced intracellular mycobacterial growth by blocking the mycobactericidal effect of 4-(Benzyloxy)phenol. Altogether, the results showed that 4-(Benzyloxy)phenol executed its anti-mycobacterial effect by modulating p53-mediated ROS production to regulate phagosome-lysosome fusion through Ca2+ production. 

4-(Benzyloxy)phenol-induced p53 exhibits antimycobacterial response triggering phagosome-lysosome fusion through ROS-dependent intracellular Ca2+ pathway in THP-1 cells

Tweaking host immune responses for novel therapeutic approaches against Mycobacterium tuberculosis.

Coronavirus disease‐19 (COVID‐19) is caused by severe acute respiratory syndrome coronavirus ‐2 (SARS‐CoV‐2) and is responsible for a higher degree of morbidity and mortality worldwide. There is a smaller number of approved therapeutics available to target the SARS‐CoV‐2 virus, and the virus is evolving at a fast pace. So, there is a continuous need for new therapeutics to combat COVID‐19. The main protease (Mpro) enzyme of SARS‐CoV‐2 is essential for replication and transcription of the viral genome, thus could be a potent target for the treatment of COVID‐19. In the present study, we performed an in‐silico screening analysis of 400 diverse bioactive inhibitors with proven antibacterial and antiviral properties against Mpro drug target. Ten compounds showed a higher binding affinity for Mpro than the reference compound (N3), with desired physicochemical properties. Furthermore, in‐depth docking and superimposition revealed that three compounds (MMV1782211, MMV1782220, and MMV1578574) are actively interacting with the catalytic domain of Mpro. In addition, the molecular dynamics simulation study showed a solid and stable interaction of MMV178221‐Mpro complex compared to the other two molecules (MMV1782220, and MMV1578574). In line with this observation, MM/PBSA free energy calculation also demonstrated the highest binding free energy of −115.8 kJ/mol for MMV178221‐Mpro compound. In conclusion, the present in silico analysis revealed MMV1782211 as a possible and potent molecule to target the Mpro and must be explored in vitro and in vivo to combat the COVID‐19.

A Drug Repurposing Approach to Identify Therapeutics by Screening Pathogen Box Exploiting SARS‐CoV‐2 Main Protease

Role of transcription termination factor Rho in anti-tuberculosis drug discovery.

Exploring the Plausible Role of Aurora Kinase A in Epstein-Barr Virus Mediated Gastric Cancer Progression

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Tweaking host immune responses for novel therapeutic approaches against Mycobacterium tuberculosis.

A Drug Repurposing Approach to Identify Therapeutics by Screening Pathogen Box Exploiting SARS‐CoV‐2 Main Protease

Role of transcription termination factor Rho in anti-tuberculosis drug discovery.

Exploring the Plausible Role of Aurora Kinase A in Epstein-Barr Virus Mediated Gastric Cancer Progression