The emergence of convergent multidrug-resistant (MDR) and hypervirulent (hvKp) lineages has transformed Klebsiella pneumoniae into a major global health threat. Frequently associated with hospital-acquired pneumonia, bacteremia, urinary tract infections (UTIs), meningitis, and sepsis, these strains disproportionately affect elderly, immunocompromised, and critically ill patients, resulting in high morbidity and mortality. Their rapid dissemination has further intensified the global antimicrobial resistance (AMR) crisis, highlighting the urgent need for therapeutic strategies beyond conventional antibiotics. Although bacteriophages have demonstrated considerable potential as antibacterial agents, their successful clinical application depends on factors extending beyond bacterial eradication alone. This review critically integrates current evidence on therapeutic efficacy, host-phage immune interactions, delivery optimization, phage-antibiotic synergy, phage-derived therapeutics, AI-assisted phage discovery, and translational considerations within a unified framework for K. pneumoniae infections. It further examines how these interconnected determinants collectively influence therapeutic outcomes and discusses emerging strategies for precision phage therapy. By adopting this integrated translational perspective, the review identifies the key factors governing successful clinical implementation and provides a framework for advancing bacteriophage therapy against multidrug-resistant K. pneumoniae infections.

Uropathogenic Escherichia coli (UPEC) remains the principal driver of urinary tract infections (UTIs), utilizing sophisticated immunoevasive strategies that consistently outmaneuver host defenses and conventional clinical management. This review synthesizes current evidence highlighting the development of recurrent UTIs (rUTIs). Particular emphasis is given to the transition of UPEC into intracellular bacterial communities (IBCs) and quiescent intracellular reservoirs (QIRs)—survival phenomena primarily characterized across specialized mammalian and cellular models. By highlighting the translational evidence gaps surrounding these intracellular sanctuaries, and the challenge of directly extrapolating these model-derived dynamics to human recurrent UTIs (rUTIs), alongside the role of extra-urinary niches, we provide a comprehensive view of the mechanisms driving recurrence. A critical assessment of the UPEC virulence arsenal, involving molecular mechanisms that regulate fimbrial phase variation resulting in evading host immune surveillance, to specialized adhesins, like FimH, which tightly bind uroplakin receptors, triggering host actin rearrangements via rho-GTPase signaling and facilitating bacterial internalization, is also addressed. Additionally, we integrate the roles of cytotoxic necrotizing factor-1 (CNF1) and hemolysin A (HlyA) in promoting cytosolic escape, host cell survival, and long-term persistence. Finally, this review presents a multidisciplinary framework evaluating next-generation non-antibiotic strategies, including bacteriophage therapy, vaccines, phytotherapy, probiotics, and estrogen therapy. By critically assessing their efficacy and clinical maturity across a spectrum of preclinical models and human trials, we evaluate the potential to navigate translational limitations to effectively disrupt the infection cycle.

The mammalian immune system has evolved in constant dialogue with its diverse microbiota, forming an ecological and molecular partnership that is fundamental to health. This review examines how microbial communities shape immunity across developmental and functional axes, the immunological consequences of dysbiosis during infection and inflammatory disease, and emerging microbiota-targeted interventions. The host–microbiota–pathogen triad offers a framework to understand how commensals and pathogens compete for ecological niches and immune recognition, and how disturbances in this balance can cascade into chronic inflammation or infection. Microbial metabolites such as short-chain fatty acids, secondary bile acids, and tryptophan derivatives act as key bioactive intermediaries translating microbial activity into host immune architecture, influencing epigenetic programming, cellular differentiation, and mucosal barrier function. These interactions orchestrate tolerance toward commensals while maintaining effector readiness against pathogens, particularly through regulatory T cell (Treg)–Th17 balance, B cell education, and Immunoglobulin A (IgA) responses. When perturbed, as in infections caused by Clostridioides difficile, Klebsiella pneumoniae, Salmonella enterica, or Listeria monocytogenes, the ensuing dysbiosis reinforces immune dysfunction in a self-perpetuating cycle. Therapeutic frontiers now extend beyond conventional antimicrobial strategies to include live biotherapeutics, bacteriophage therapy, fecal microbiota transplantation, and metabolite-based (postbiotic) interventions. Future efforts must reconcile inter-individual microbiome variability with precision medicine, integrating metagenomic and metabolomic profiling to design safe, effective, and personalized microbiota-centered therapeutics.

Microbial spoilage by Pseudomonas fluorescens and Pseudomonas putida remains a critical challenge in the dairy industry, particularly in refrigerated environments, where traditional preservation methods face limitations. This study demonstrates the biocontrol potential of P. fluorescens and P. putida-specific novel bacteriophages, AM.PF and AM.PP. Phage characterization confirmed them as safe, lytic dsDNA phages devoid of antimicrobial resistance genes, toxins or lysogenic markers, exhibiting stability across wide pH (3–11) and temperature (4°C–70°C) ranges. Both phages inhibited biofilm formation (83% and 77%) and disrupted established biofilms (42% and 54%). When phages were encapsulated in a 12% gelatin matrix, sustained release reached 77% (AM.PF) and 70% (AM.PP). Notably, the bioactive gelatin coatings reduced P. fluorescens and P. putida by 92% and 89% on cheese surfaces and by 48.8% and 92.5% in refrigerated milk, respectively. These findings demonstrate that phage-incorporated biomaterials offer a safe, highly effective strategy for food preservation.

Pathogenic microbes utilize virulence strategies to subvert host immune responses, highlighting a continuous race between the pathogen and the host. The emergence of multidrug- resistant and hypervirulent strains of Klebsiella pneumoniae (Kp) poses a critical threat to public health. This critical evaluation identifies key gaps in understanding the interplay between Kp and host innate immunity. This review provides a comprehensive overview of the mechanisms by which Kp triggers various forms of cell death. Dysregulated cell death may exacerbate cytokine release, contributing to the hyperinflammatory response characteristic of sepsis. The rise in antimicrobial resistance (AMR) in Kp necessitates the exploration of alternative therapeutic approaches. This review highlights that immunomodulatory approaches targeting cell death regulators or immune checkpoints may offer host-directed strategies against Kp-induced sepsis. Although novel immunotherapies offer potential to restore immune balance, their clinical applicability remains constrained by limited translational evidence.

Invasive fungal diseases (IFDs) are a global health threat, especially among immunocompromised populations, due to their high mortality rates and the increasing prevalence of antifungal resistance. In recognition of this threat, the World Health Organization (WHO) has designated Cryptococcus neoformans, Candida auris, Aspergillus fumigatus, and Candida albicans as critical-priority fungal pathogens. During host infection, host-derived reactive oxygen species (ROS) function as potent antimicrobial molecules, whereas fungal-derived ROS act as intracellular signaling mediators regulating oxidative stress adaptation, metabolism, virulence, and antifungal tolerance. Although oxidative stress responses have been extensively investigated in individual fungal pathogens, a comprehensive comparative analysis of oxidative stress signaling across these critical fungal pathogens remains limited. This review systematically compares oxidative stress sensing and signaling networks in the four WHO critical-priority fungal pathogens and classifies oxidative stress-associated pathways into conserved, and species-specific regulatory mechanisms. Conserved pathways, including HOG-MAPK, calcineurin, cAMP-PKA, cell wall integrity, and thioredoxin-dependent signaling, are discussed alongside pathogen-specific adaptations that promote biofilm formation, capsule and melanin production, polarized growth, morphogenesis, immune evasion, and antifungal resistance. By integrating conserved and divergent oxidative stress signaling mechanisms, this review provides a comparative framework that advances our understanding of fungal pathogenesis and highlights potential targets for the development of broad-spectrum and species-specific antifungal therapies.

Neutrophil Extracellular Traps (NETs) are web-like structures composed of DNA fibers, histones, and granular proteins released by the neutrophils activated upon various stimuli. Recognized as a host immune defense mechanism, NETs also play a significant role in several diseases, especially in bacterial infections. Research indicates that excessive NET formation contributes to various pathological outcomes, including multiple organ dysfunction. Once activated, NETs generally remain in a hyperinflammatory phenotype. In this review, we delineate how bacterial pathogens both induce excessive NET formation, driving endothelial dysfunction, and evade NET-mediated antimicrobial defense. Here, we critically examine the signaling crosstalk between the NET formation with other cell death pathways, particularly focusing on the ROS-mediated PAD4-RIPK axis as well as the gasdermin-D mediated lytic signaling. Developing therapeutic strategies that target NET function presents significant challenges, requiring a balance between maintaining beneficial aspects and eliminating harmful effects. Given the rise in antimicrobial resistance, targeting host factors could lead to the development of more effective strategies. Together, this review explores the molecular mechanisms of NET formation, the paradoxical roles of NETs in different bacterial infections, their interplay with other cell death pathways, their impact on sepsis, and the exploration of different components of NETs as potential therapeutic candidates.

Mycobacterium tuberculosis (Mtb) continues to pose a significant global health risk, primarily due to its capacity to modulate host immune responses and achieve prolonged persistence. Recent evidence has increasingly underscored the significance of epigenetic reprogramming as a principal mechanism through which Mtb modifies host cellular functions without altering the fundamental DNA sequence. This review gives a full picture of how Mtb secretory proteins work as nucleomodulins to directly target host chromatin and control gene expression. Mtb uses special secretion systems, such as the ESX (Type VII) and SecA2 pathways, to enable effector proteins to enter host cells. Some of these proteins move to the nucleus and interact with machinery that is linked to chromatin. These nucleomodulins facilitate various epigenetic modifications, encompassing non-canonical histone methylation, DNA methylation, and the modulation of histone acetylation, resulting in extensive transcriptional reprogramming of immune-related genes. These changes make important host defence mechanisms less effective, such as macrophage activation, antigen presentation, cytokine production, and antimicrobial responses. This helps bacteria survive and avoid the immune system. Epigenetic remodeling also affects the polarization and metabolic states of macrophages, which further affect the progression of disease. The reversible characteristics of epigenetic modifications offer a significant prospect for host-targeted therapeutic strategies. Targeting enzymes such as histone deacetylases and DNA methyltransferases has shown potential in restoring immune function and enhancing bacterial clearance, particularly when used in combination with conventional anti-tubercular therapies. Even with these improvements, there are still big problems with fully understanding the functional diversity of Mtb secretory proteins and turning these discoveries into useful medical tools. In general, understanding how Mtb-secreted nucleomodulins and host epigenetic regulation interact is important for understanding how tuberculosis works and finding new ways to treat it.

Candida albicans is a deadly fungal pathogen, particularly in immunocompromised individuals, where a simple superficial infection rapidly transforms into life-threatening systemic candidiasis. Virulence factors of C. albicans include the yeast-to-hyphae transition, biofilm formation, and protease production, which are crucial for establishing infection. Targeting virulence factors is a promising strategy to combat C. albicans infections, which can overcome the limitations of conventional treatment modalities. Essential oils are important in this regard as they are used in traditional medicine due to their antimicrobial capabilities. This study is focused on the antivirulent activity of cumin essential oil (CEO), which significantly reduced the key virulence factors of C. albicans, such as germ tube formation and protease production. A subinhibitory concentration (0.015% v/v) of CEO downregulated the expression of the HWP1, ALS3, and RAS1 genes involved in regulating virulence. In silico studies demonstrated that major compounds of CEO interacted with key amino acid residues of secreted aspartyl proteases (Sap4, Sap5, Sap6) and heat shock protein (Hsp90), a regulator of hyphal formation. CEO significantly reduced biofilm formation of C. albicans in different simulated body fluids such as saliva, artificial urine, and tear fluid. Furthermore, CEO affected the host-pathogen interaction of C. albicans with THP-1 macrophages by increasing phagocytosis and inhibiting germ tube formation. Additionally, CEO treatment modulated the levels of pro-inflammatory and anti-inflammatory cytokines, suggesting that CEO also has immunomodulatory properties, in addition to its antivirulence activity. These results indicate that CEO could be a promising candidate for combating C. albicans infections.

Ocular infections are a major cause of morbidity and vision loss worldwide, significantly affecting the quality of life and clinical outcomes. The management of ocular infections has become increasingly difficult due to the rising prevalence of antimicrobial resistance among commonly implicated pathogens. This review summarizes the epidemiology and etiology of ocular infections, with emphasis on bacterial pathogens frequently associated with resistance. Various mechanisms of antimicrobial resistance, including genetic mutations, intrinsic resistance, and biofilm formation, are also discussed. The review further examines the limitations of current therapeutics, such as poor ocular drug penetration, frequent dosing requirements, adverse effects, and reduced efficacy against multi-resistant organisms. In response to these challenges, the need for novel therapeutic approaches with improved stability and prolonged ocular retention is highlighted. Furthermore, the integration of artificial intelligence in ophthalmology is explored, particularly in disease diagnosis, image analysis, treatment planning, and antimicrobial resistance surveillance. Despite these advances, several translational challenges remain, including data set bias, limited external validation, regulatory approval hurdles, data privacy concerns, and restricted accessibility in resource-limited settings, which currently limit the widespread clinical implementation. Therefore, continued surveillance, rational antimicrobial use, and effective therapeutic strategies are essential to reduce the burden of ocular infections and improve patient outcomes.

Vaccination stands as one of the most transformative interventions in the history of human civilization. In medicine, vaccination stands as a cornerstone that has saved countless lives across generations. Nevertheless, conventional vaccine development remains encumbered by prolonged timelines, substantial financial investment, and high attrition rates particularly during late-stage clinical trials underscoring the urgent need for more efficient and systematic approaches. In recent years, artificial intelligence (AI) has emerged as a transformative force across the biomedical sciences, offering unprecedented computational capacity to process and interpret complex biological datasets. The convergence of AI with vaccinology represents a significant methodological advancement which has the potential to fundamentally redefine the vaccine development paradigm. AI integrates advances in machine learning, multi-omics data analysis, and high-performance computing to accelerate antigen discovery, epitope prediction, immunogen design, and clinical evaluation. This development represents a paradigm shift toward faster, more precise, and scalable strategies for vaccine development. This review critically examines the current landscape of AI applications in vaccine development, with particular emphasis on recent advancements, translational challenges, and the prospective role of AI in shaping the future of immunization science.

The global emergence of multidrug-resistant (MDR) and hypervirulent (hvKp) Klebsiella pneumoniae strains poses a major clinical challenge. Here, we compared representative classical (cKp), MDR-Kp, and hvKp isolates to define host epigenetic responses during infection. At 24 h post-infection (hpi), infection with all three strains induced HDAC2 upregulation and H3K18 deacetylation, with chromatin immunoprecipitation (ChIP) analysis revealing HDAC2 enrichment at the ATG5 promoter, linking epigenetic remodeling to autophagy suppression. Functionally, cKp and MDR-Kp isolates promoted M1-like macrophage polarization, whereas hvKp isolate induced an immunosuppressive M2-like phenotype associated with enhanced intracellular bacterial survival and elevated IL-10 expression. HDAC1/2 gene knockdown reduced intracellular bacterial survival, while pharmacological inhibition using CI994 and SAHA restored autophagy, normalized cytokine responses, enhanced bacterial clearance, and reversed M2-like polarization induced by hvKp-isolate. Collectively, these findings identify HDAC-mediated epigenetic reprogramming as a central mechanism underlying immune evasion during K. pneumoniae infection and support HDAC inhibition as a potential host-directed therapeutic strategy.

Hospital surfaces, particularly in intensive care units (ICUs), often harbor Pseudomonas aeruginosa, a notorious, opportunistic pathogen capable of surviving on fomite surfaces and forming highly resilient biofilms, presenting a significant infection control challenge. To address this, our study investigates bacteriophages as a targeted disinfection strategy, focusing on the isolation and characterization of four novel phages-AM.P2, AM.P3, AM.P4 and AM.P5 for their potential to eradicate biofilms on fomites from ICU settings. Genomic analysis revealed all the phages to be novel, dsDNA phages, lacking AMR and virulence genes. AM.P3 and AM.P5 are jumbo phages (280.1 kb and 279.9 kb, respectively), in contrast to AM.P4 (73.2 kb), which was similar to AM. P2. All phages exhibited robust physicochemical stability over a wide range of temperatures and pH (4-60 degrees C; pH:4-10). The disinfection potential of the phages on planktonic bacteria, evaluated on steel and tile surfaces from ICU settings, demonstrated significant inhibition potential (80-98 % and 81-100 % respectively). Additionally, all the phages and phage cocktail also exhibited significant inhibition of biofilm formation (67-79 %), as well as disruption of established mature biofilms (43-70 %) on steel surfaces. Furthermore, a comparative study with two commonly used chemical disinfectants in ICUs, demonstrated that sequential treatment with phage, followed by disinfectant, resulted in enhanced disruption of mature biofilm on fomite surfaces from ICUs, as compared to phage or disinfectant individually, highlighting an effective translational approach for the use of phages to enhance the efficacy of disinfectants.

ObjectiveTo evaluate the clinical severity and microbiological characteristics of participants with type 2 diabetes and foot ulcers (DFUs) screened for eligibility into a bacteriophage therapy pilot study.Research Design And MethodsAdults aged (≥18 years) with type 2 diabetes mellitus (T2DM) and active DFUs presenting to a tertiary care centre were screened using predefined eligibility criteria. Ulcers were graded according to the University of Texas Diabetic Foot Classification System. Microbiological analysis included standard culture techniques and biochemical tests for identification of microorganism. Descriptive statistics were used to summarize ulcer severity, microbial patterns, and eligibility outcomes.ResultsA total of 595 individuals were screened. Grade 3 ulcers accounted for 51.1% of cases, followed by Grade 2 (29.1%) and Grade 1 (19.8%). Monomicrobial infections were identified in 63.7% of individuals, polymicrobial infections in 17.6%, and no growth in 18.7%. Gram-negative organisms predominated, including Pseudomonas spp. (n = 74), Escherichia spp. (n = 60), Klebsiella spp. (n = 50), Proteus spp. (n = 43), and Acinetobacter spp. (n = 25). Among Gram-positive organisms, Staphylococcus spp. (n = 81) and Enterococcus spp. (n = 43) were common.ConclusionsThe screened population demonstrated a high burden of advanced Grade 3B DFUs, predominantly associated with Gram-negative pathogens amenable to bacteriophage targeting. But this pilot study intentionally focused on Grade 1B and Grade 2B ulcers to assess the feasibility and safety of bacteriophage therapy in predefined, less severe DFUs. This pre-screening process supported the feasibility and enrollment of eligible participants for the subsequent bacteriophage therapy pilot study.

Post-translational modifications (PTMs) serve as essential regulatory mechanisms that fine-tune protein function, stability, localization, and interaction networks, enabling cells to adapt rapidly to physiological and pathological cues. Among the diverse PTMs, SUMOylation—the covalent attachment of Small Ubiquitin-like Modifier (SUMO) proteins to specific lysine residues on target substrates—has emerged as a dynamic and reversible modification with far-reaching implications in cellular homeostasis. Beyond its well-established roles in transcriptional regulation, DNA repair, and stress responses, recent studies highlight how pathogens have evolved to hijack the host SUMOylation machinery to subvert immune signalling, dampen inflammatory responses, and enhance intracellular survival. This review delves into the multifaceted role of SUMOylation in infectious disease, emphasizing its interplay with key host signalling cascades/axes such as NF-κB, MAPK, JAK-STAT, and interferon pathways. We explore how bacterial, viral, and fungal pathogens manipulate SUMOylation to reprogram host chromatin, modulate vesicular trafficking, and evade cytokine-mediated defences. Additionally, we examine the crosstalk between SUMOylation and other PTMs—such as ubiquitination, phosphorylation, and acetylation—that collectively shape the host-pathogen interface. By synthesizing current evidence on pathogen-driven SUMO modulation, we offer an integrated view of how this modification governs immune outcomes. Lastly, we evaluate emerging therapeutic strategies aimed at targeting SUMOylation pathways through small molecule inhibitors and genetic tools, with the goal of restoring immune competence and mitigating persistent infections. These insights position SUMOylation as a critical regulatory node and a promising target for host-directed therapies against infectious diseases.

Pyomelanogenic P. aeruginosa, frequently isolated from patients with urinary tract infections and cystic fibrosis, possesses the ability to withstand oxidative stress, contributing to virulence and resulting in persistent infections. Whole genome sequence analysis of U804, a pyomelanogenic, multidrug-resistant, clinical isolate, demonstrates the mechanism underlying pyomelanin overproduction. Seven essential oils (EOs) were screened for pyomelanin inhibition. Garlic, cinnamon and thyme EOs were selected for further studies based on their significant anti-virulent properties, like inhibition of pyomelanin production and biofilm formation. Additionally, downregulation of the expression of virulence genes regulated by quorum sensing (QS) and a decrease in levels of the QS signaling molecule, C12-HSL, were also observed. The EO treatment inhibited the survival of U804 in human blood and increased survival of C. elegans, a whole animal model of pathogenesis. EO treatment also resulted in a significant reduction of efflux pump activity, indicative of their effect on antibiotic sensitization. Garlic oil enhanced the permeability of the bacterial membrane, resulting in decreased survival, when combined with sub-MIC concentrations of colistin. This study demonstrates that thyme, cinnamon and garlic EOs can attenuate pyomelanogenic P. aeruginosa virulence traits. Additionally, garlic potentiates drug sensitivity, suggesting its promising therapeutic use in combating pyomelanogenic MDR infections.

This research focuses on designing a novel, five-layered N95 mask fabric that integrates the natural antimicrobial properties of Boswellia serrata, thereby unlocking a new dimension in respiratory protection. Specifically, the second and third layers of the mask fabric were coated with a chloroform extract of Boswellia serrata to impart layer-specific functionality. The functionalized mask fabrics underwent rigorous analysis, including Scanning Electron Microscopy (SEM), Energy Dispersive X-ray (EDX) Spectroscopy, Fourier Transform Infrared Spectroscopy (FTIR), and wettability measurements, confirming the successful incorporation of the extract. The contact killing assay demonstrated a highly effective dual-action defense system. The extract-coated second layer exhibited a rapid, but transient, antimicrobial effect, showing excellent inhibition within one hour (92% against S. aureus, 86% against E. aerogenes), though this effect diminished significantly by eight hours. In contrast, the third layer provided a prolonged and sustained antimicrobial effect, maintaining high inhibition even after eight hours (100% against C. albicans and K. pneumoniae, and 90% against E. aerogenes). Maximum killing efficiency was observed at four hours for both layers. This innovative application of layer-specific engineering offers enhanced and prolonged protection against airborne pathogens, marking a significant leap in mask technology.

The global rise in multidrug-resistant (MDR) Klebsiella pneumoniae, a critical ESKAPE pathogen, has outpaced the development of effective antibiotics. Bacteriophage therapy offers a promising alternative, but therapeutic candidates must be carefully selected for broad activity, genetic safety, synergistic cocktail performance, and clinical stability. We isolated and characterized six novel lytic phages (vB_Kpn_AM.K1 to vB_Kpn_AM.K6) targeting K. pneumoniae by assessing morphology, host range, growth kinetics, physicochemical stability, and resistance frequency. Genomes were sequenced to confirm absence of lysogeny and virulence genes. Infection dynamics was visualized via fluorescence microscopy. Phage activity was tested across 60 different MDR K. pneumoniae clinical isolates, obtained from diverse sources such as blood, sputum, occult feces, urine etc. All six isolated phages were identified as novel dsDNA phages belonging to Caudoviricetes, with genome sizes ranging from 111 to 169 Kbp, devoid of virulence and AMR genes and demonstrating strong bacteriolytic activity. Growth kinetics indicated burst sizes varying from 12-148 PFU/infected cell. The phages displayed stability between 4-50°C, pH 4 -10 and sustained complete activity after lyophilization. More significantly, the phages and their cocktail combinations could effectively kill 93

Mycobacterium tuberculosis, the etiological agent of tuberculosis, is a significant worldwide health threat, especially in resource-limited environments. This review emphasizes that manipulating host metabolic and epigenetic pathways can bolster immune defences and potentially shorten the duration of tuberculosis treatment. The growing prevalence of multidrug-resistant TB and the protracted nature of standard treatments underscore the urgent need for alternative therapeutic approaches. Host-directed treatment has arisen as a promising approach that aims to enhance or redirect the host's innate and adaptive responses rather than targeting the pathogen directly. This strategy focuses on counteracting M. tuberculosis-induced subversion of immune and cellular processes. Approaches under investigation include modulation of host metabolic pathways, stimulation of autophagy, epigenetic reprogramming, and strengthening of immune defense mechanisms to control or eliminate infection. These interventions hold potential for not only overcoming traditional drug resistance but also for accelerating recovery and reducing immunopathology. In this review, we explore recent advances in host-directed therapy research, with particular emphasis on mechanisms involving immunometabolic regulation, epigenetic remodeling, and enhancement of intercellular antimicrobial responses. The advancement of these methodologies may facilitate the creation of more accurate and efficacious tuberculosis treatments. We highlight recent work on three linked areas-immunometabolic regulation, epigenetic control, and autophagy driven antimicrobial activity drawing out the main advances and remaining debates that guide future host-directed approaches. Viewing host-directed therapy through this integrated lens outline a path toward more targeted, durable, and resistance-resilient interventions for tuberculosis.

Rv1899c, a previously identified HDAC1–ZBTB25-interacting protein of Mycobacterium tuberculosis, plays a crucial role in bacterial adaptation and immune modulation. Recombinant M. smegmatis-expressing Rv1899c (MS_ Rv1899c) showed enhanced survival under acidic and oxidative stress compared to vector controls, along with improved early intracellular growth in THP1-derived macrophages. This was accompanied by reduced reactive oxygen species (ROS), diminished cytokines associated with inflammation and downregulation of autophagy proteins ATG5, Beclin, and LC3, which ultimately skewed the immune response, suppressing the pro-inflammatory M1 macrophage population. Targeting Rv1899c with 3-aminobenzamide (3-AB) impaired intracellular bacterial survival and restored IL-12B expression, while its combination with the HDAC inhibitor C1994 significantly enhanced bacterial clearance. Structural modelling confirmed the high stereochemical quality of the Rv1899c macrodomain, and computational studies identified 3-AB as the strongest ligand (−5.75 kcal/mol), stabilized through hydrogen bonding and hydrophobic interactions with key residues. Molecular dynamics simulations conducted for 200 ns demonstrated stable protein–ligand interactions with consistent parameters, while MM/GBSA analysis indicated favourable binding energy (ΔG_bind = −6.6 kcal/mol), largely influenced by van der Waals and electrostatic forces. Together, these findings highlight Rv1899c as a mediator of stress resistance and immune evasion and propose it as a potential therapeutic target against M. tuberculosis.