Journal of Bacteriology最新文献

{"title":"Impaired acid stress resistance in <i>Salmonella</i> Typhi Ty2.","authors":"Kiranmai Joshi, Wai Yee Fong, Marie-Pierre Blanc, Fermin E Guerra, Ferric C Fang","doi":"10.1128/jb.00197-26","DOIUrl":"10.1128/jb.00197-26","url":null,"abstract":"<p><p><i>Salmonella enterica</i> encounters acid stress during gastrointestinal transit and within the phagosomal environment of macrophages. Acid stress resistance has been well characterized in <i>Salmonella enterica</i> serovar Typhimurium, but comparative studies in the human-adapted <i>Salmonella enterica</i> serovar Typhi are limited. We compared the growth of <i>S</i>. Typhimurium 14028s and <i>S</i>. Typhi Ty2 at pH values ranging from 3 to 8 and observed that <i>Salmonella enterica</i> serovar Typhimurium exhibits enhanced growth at pH 4.5 compared to <i>S</i>. Typhi. Comparative transcriptomic profiling of <i>S</i>. Typhimurium and <i>S</i>. Typhi at pH 4.5 and 7.5 identified numerous differentially expressed acid-induced genes (DEGs), including genes encoding membrane proteins (OmpC, PhoE, HydB), a transcriptional regulator (RpoS), and stress response proteins (YciG, STM14_1829, YmdF). Targeted deletion of selected genes in <i>S</i>. Typhimurium significantly suppressed growth at acidic pH, confirming their role in acid stress resistance. These resistance mechanisms are compromised in <i>S</i>. Typhi due to pseudogenization. Heterologous expression of pseudogenized genes in <i>S</i>. Typhi restored acid tolerance. Collectively, these findings suggest that <i>S</i>. Typhi has lost the ability to withstand acid stress due to genomic decay and the loss of multiple genes essential for acid survival in <i>S</i>. Typhimurium, reflecting divergent evolutionary paths in these two serovars.</p><p><strong>Importance: </strong><i>Salmonella</i> Typhimurium must adapt to acidic pH conditions in the intestinal tract and the intracellular environment to cause infection. In this study, we show that the enteric fever serovar <i>Salmonella</i> Typhi exhibits impaired growth at pH 4.5 in comparison to <i>Salmonella</i> Typhimurium. We further show that the loss of specific membrane proteins, a transcriptional regulator, and a family of stress response proteins in <i>Salmonella</i> Typhi are responsible for this difference. Collectively, these observations suggest that <i>Salmonella</i> Typhi has evolutionarily lost the ability to withstand acid stress due to differences in its interaction with the human host. This has important implications for the pathogenesis of typhoid fever.</p>","PeriodicalId":15107,"journal":{"name":"Journal of Bacteriology","volume":" ","pages":"e0019726"},"PeriodicalIF":3.8,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149024887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction for Dufour et al., \"Quorum sensing rewires membrane vesicle protein cargo to promote antibiotic persistence in <i>Streptococcus mutans</i>\".","authors":"Delphine Dufour, Camila Leiva-Sabadini, Sebastian Aguayo, Céline M Lévesque","doi":"10.1128/jb.00468-26","DOIUrl":"10.1128/jb.00468-26","url":null,"abstract":"","PeriodicalId":15107,"journal":{"name":"Journal of Bacteriology","volume":" ","pages":"e0046826"},"PeriodicalIF":3.8,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148989743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How <i>Bdellovibrio bacteriovorus</i> became a model for invasive bacterial predation.","authors":"Andrew L Lovering, R Elizabeth Sockett","doi":"10.1128/jb.00137-26","DOIUrl":"10.1128/jb.00137-26","url":null,"abstract":"<p><p><i>Bdellovibrio bacteriovorus</i> is a gram-negative Proteobacterium that has evolved to use a novel, predatory, intrabacterial lifestyle. Once encountered under a microscope, in a lecture, or a textbook, it is seldom forgotten. <i>B. bacteriovorus</i> speedily collides with, enters, modifies, and kills other gram-negative bacteria. Residing inside the periplasm of the dead prey for several hours, it uses prey molecules for growth and replication, only bursting out from that temporary home when its progeny are fully formed predators themselves. Rapid motility whilst hunting contrasts with sessility during prey consumption-these key behaviors, studied by early researchers, have been followed by molecular studies in recent times. Genomic analysis has enabled the linkage and discovery of proteins involved in key regulatory circuits, allied to enzymology describing prey cell manipulation and deconstruction. Indeed, the prey bacterium of a <i>B. bacteriovorus</i> is the natural \"petri dish\" of suitable components for predator growth. A fascinating <i>B. bacteriovorus</i> conundrum continues to be: \"how does a predator consume materials very similar to those from which it is built, without self-damage?\". More has been discovered and is yet to be learned about these bacterial damaging enzymes: how predators use them in nature and whether they can be applied to assist human conflicts with pathogens. However, the elegance and molecular complexity, with which <i>B. bacteriovorus</i> accomplishes its intrabacterial lifestyle, will continue to challenge researchers and present new biology in the 21st century. New discoveries, tools, and approaches position <i>B. bacteriovorus</i> research for many more breakthroughs.</p>","PeriodicalId":15107,"journal":{"name":"Journal of Bacteriology","volume":" ","pages":"e0013726"},"PeriodicalIF":3.8,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148989678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The status of RpoS impacts the 2-aminoacrylate stress paradigm in <i>ridA</i> mutants of <i>Salmonella enterica</i> serovar Typhimurium.","authors":"Andrea Giuliano, Jessica K Novak, Diana M Downs","doi":"10.1128/jb.00390-26","DOIUrl":"10.1128/jb.00390-26","url":null,"abstract":"<p><p>Bacterial metabolism is composed of a complex system of anabolic and catabolic processes, and productive growth results from the regulated interplay of these processes. Genetic and biochemical studies on the LT2 type strain of <i>Salmonella enterica</i> serovar Typhimurium determined the need for RidA to prevent metabolic stress caused by 2-aminoacrylate (2AA). RidA is an enamine deaminase, and in its absence, 2AA accumulates and can irreversibly damage critical pyridoxal 5'-phosphate-dependent enzymes. Unexpectedly, the disruption of <i>ridA</i> in a virulent type strain (<i>S. enterica</i> serovar Typhimurium strain 14028s) did not replicate the serine sensitivity observed in LT2. Consistent with reported differences between these strains, the status of <i>rpoS</i> impacted the phenotypes caused by a <i>ridA</i> mutation. Specifically, serine sensitivity in the 14028s strain background occurred only when an insertion in <i>rpoS</i> was combined with a mutation in <i>ridA</i>. Further data suggest the 14028s <i>rpoS ridA</i> growth deficiency is due to poor expression of <i>sdaA</i>, which encodes an Fe-S cluster serine deaminase. Additional combinatorial effects of lesions in <i>ridA</i> and <i>rpoS</i> indicate that the functional status of RpoS modulates the metabolic network in multiple ways that impact the cellular response to 2AA.IMPORTANCERidA is an enamine/imine deaminase known for mediating 2-aminoacrylate (2AA)-induced stress in several bacterial models. Best characterized in <i>S. enterica</i>, manipulations to RidA have been used to probe metabolic flux in various bacteria. Here, we find that a key factor in the manifestation of 2AA stress is the status of transcriptional regulator RpoS. Our results indicate that a functional RpoS mediates some of the stress induced by exogenous serine in a <i>ridA</i> mutant strain and further implicates this regulator in modulating the metabolic network. These results bolster our understanding of the flux and robustness integral to bacterial metabolism and emphasize a need to better understand the involvement of the RpoS regulon.</p>","PeriodicalId":15107,"journal":{"name":"Journal of Bacteriology","volume":" ","pages":"e0039026"},"PeriodicalIF":3.8,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An integrated view of metabolic and physiological regulation of toxin production in <i>Clostridioides difficile</i>.","authors":"Chetna Dureja, Ann M McKelvey, Julian G Hurdle","doi":"10.1128/jb.00318-26","DOIUrl":"10.1128/jb.00318-26","url":null,"abstract":"<p><p><i>Clostridioides difficile</i> is a leading cause of antibiotic-associated diarrhea, with pathogenesis driven primarily by the glucosylating toxins TcdA and TcdB. Traditionally, toxin gene expression has been explained through regulation of the pathogenicity locus by global transcriptional regulators that integrate nutrient availability, growth phase, and environmental signals. While this framework provides a foundation for understanding toxin regulation, recent advances have broadened this perspective to include diverse metabolic and physiological inputs, including carbon and amino acid metabolism, metal ion homeostasis, redox balance, and cellular energy status. Collectively, these factors suggest that toxin gene expression is a dynamic emergent property that reflects a high level of integration of metabolic and physiological networks. In this minireview, we discuss canonical mechanisms of toxin regulation alongside new insights that highlight population heterogeneity, energy demand conflicts, metabolic constraints, purine metabolism, and cross-regulatory networks linking sporulation and virulence. We further examine discoveries from small-molecule chemical genetics demonstrating that perturbation of metabolic pathways can suppress toxin biosynthesis without substantially affecting bacterial viability. Together, these findings redefine toxin regulation as a systems-level process in which metabolic and physiological states mediate toxin production and contribute to phenotypic heterogeneity. Elucidating these networks may reveal promising targets for the development of anti-virulence strategies for <i>C. difficile</i> infection.</p>","PeriodicalId":15107,"journal":{"name":"Journal of Bacteriology","volume":" ","pages":"e0031826"},"PeriodicalIF":3.8,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148963122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Components of the Clp complex are required for sporangium formation and dehiscence in <i>Actinoplanes missouriensis</i>.","authors":"Ryota Suzuki, Manato Maruko, Remi Suzuki, Takeaki Tezuka, Yasuo Ohnishi","doi":"10.1128/jb.00308-26","DOIUrl":"10.1128/jb.00308-26","url":null,"abstract":"<p><p>The actinomycete <i>Actinoplanes missouriensis</i> forms terminal sporangia that contain a few hundred spores. When immersed in water, the sporangium opens to release spores, which start swimming using flagella, via a process referred to as sporangium dehiscence. In this study, we conducted a functional analysis of genes encoding the components of the caseinolytic protease (Clp) complex, which comprises ATPase (chaperone) subunits (ClpX and ClpC) and proteolytic subunits (ClpP1-4). The <i>clpX</i> null mutant (Δ<i>clpX</i>) strain formed sporangia smaller than the wild-type strain. The small sporangia scarcely opened under conditions that induce sporangium dehiscence in the wild-type strain. Consistently, the number of released spores was three orders of magnitude lower in the Δ<i>clpX</i> strain than in the wild-type strain. S1 nuclease mapping determined two transcriptional start points of <i>clpX</i> (TSS_U and TSS_D for upstream and downstream, respectively). A housekeeping sigma factor-dependent promoter and a FliA-family sigma factor-dependent promoter were found upstream of TSS_U and TSS_D, respectively. A gene complementation test showed that apparently normal sporangium formation in the Δ<i>clpX</i> strain was restored by the introduction of <i>clpX</i> with either of the two promoters, whereas both promoters were required for sporangium dehiscence. Meanwhile, mutant strains that produced ClpC with T30S or I33F/L34F replacements, which presumably reduced their substrate-binding activity, produced sporangia with irregular shapes. Furthermore, gene disruption experiments of four putative proteolytic subunit genes indicated that <i>clpP3</i> is conditionally involved in sporangium dehiscence. We concluded that sporangium formation and dehiscence are regulated at the post-translational level via proteolysis by Clp complexes in <i>A. missouriensis</i>.</p><p><strong>Importance: </strong><i>Actinoplanes missouriensis</i> has a complex life cycle, in which the sporangium containing a few hundred flagellated spores is the most characteristic structure. Spores are released from sporangia via a process called sporangium dehiscence. We have revealed that sporangium formation and dehiscence are regulated by several transcriptional regulators; however, post-transcriptional regulation of sporangium formation and dehiscence remains unknown. In the present study, we revealed that two ATPase components of the Clp complex, ClpC and ClpX, and a proteolytic component, ClpP3, are involved in sporangium formation and/or dehiscence. This study indicates that in addition to transcriptional regulation, proteolysis regulated by Clp complexes is another crucial factor in the morphological development of <i>A. missouriensis</i>.</p>","PeriodicalId":15107,"journal":{"name":"Journal of Bacteriology","volume":" ","pages":"e0030826"},"PeriodicalIF":3.8,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148880523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Strain-specific outcomes of cytosine-base editing in <i>Streptomyces</i>.","authors":"Maxime M Boneza, Thomas Keller, Josephine Mostek, Michael J Smanski","doi":"10.1128/jb.00241-26","DOIUrl":"10.1128/jb.00241-26","url":null,"abstract":"<p><p>The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas system has facilitated gene editing of different organisms. Specifically, programmable base editing enables stable conversion of a single nucleotide to another nucleotide without causing DNA double-strand breaks. Cas9-derived base editors, including adenine and cytidine base editors, catalyze the formation of transition mutations with high efficiency. The third-generation cytidine base editors comprise a nickase-Cas9 fused to a cytidine deaminase and uracil DNA glycosylase inhibitor to enable the transition from C:G to T:A. We observed that in certain <i>Streptomyces</i> spp., this cytidine base editor produced C:G to G:C transversions at a surprisingly high rate of 44, while in other strains, it yielded the expected C:G to T:A transition mutations. There was also a notable timing difference for base editing between distinct strains. Bioinformatics analysis revealed differences in DNA mismatch repair and nucleotide excision repair pathways, including the presence of <i>uvrD</i> helicase gene only in the C:G to G:C transversion strain. Expression of <i>uvrD</i> in the C:G to T:A transition strain led to higher rates of C:G to G:C transversions. These discoveries will aid in the development of efficient C:G to G:C base editors.</p><p><strong>Importance: </strong>Base editors are useful tools that allow genetic engineers to precisely change single bases in an organism's genome. Most base editors catalyze transition mutations (e.g., A-to-G or C to-T). Transversion mutations, which convert a purine base to a pyrimidine base, have been described but operate at much lower efficiency. Here, we describe a surprising discovery that a transition base editor produced high-efficiency transversion mutations in a species of <i>Streptomyces</i>. This information was used to engineer a high-efficiency transversion base editor.</p>","PeriodicalId":15107,"journal":{"name":"Journal of Bacteriology","volume":" ","pages":"e0024126"},"PeriodicalIF":3.8,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural and biochemical insights into isophthalate dihydrodiol dehydrogenase from <i>Comamonas testosteroni</i> KF1.","authors":"Jai Krishna Mahto, Monica Sharma, Kuldeep Jangid, Pravindra Kumar","doi":"10.1128/jb.00233-26","DOIUrl":"https://doi.org/10.1128/jb.00233-26","url":null,"abstract":"<p><p>Isophthalate serves as a carbon and energy source for several microorganisms through a dedicated catabolic pathway, in which isophthalate dihydrodiol dehydrogenase (IphB) mediates the NAD(<i>P</i>)⁺-dependent oxidation of 1,2-dihydroxy-3,5-cyclohexadiene-1,5-dicarboxylate (1,5-DCD) to protocatechuate. Here, we present the structural and biochemical characterization of isophthalate dihydrodiol dehydrogenase (IphB_KF1) from <i>Comamonas testosteroni</i> KF1. Enzyme kinetics revealed IphB_KF1 catalyzes the dehydrogenation of 1,5-DCD substrate with both NAD⁺ and NADP⁺, exhibiting a ~4 fold higher catalytic efficiency (<i>k</i>_cat/<i>K</i>_M) with NADP⁺. Crystal structures of IphB_KF1 were determined in the apo form, in complex with NADP⁺, and as a ternary complex with NADP⁺ and the product 3,4-dihydroxybenzoic acid (3,4-DHB; protocatechuate) at resolutions of 1.5, 1.8, and 1.5 Å, respectively. Structural analysis reveals an NADP⁺-induced conformational change that facilitates cofactor accommodation and identifies key residues involved in NADP⁺ binding. Sequence and structural analyses highlight two conserved motifs, GXXXGXG and YXXXK, characteristic of the short-chain dehydrogenase/reductase (SDR) superfamily. Ternary complex of IphB_KF1 (NADP⁺ and 3,4-DHB) and molecular docking with 1,5-DCD suggests that specific active-site residues contribute to substrate recognition and underpin the distinct substrate specificity of IphB_KF1 compared to other SDR family members. Based on structural insights and comparison with homologous enzymes, we propose a catalytic mechanism for isophthalate oxidation. Together, these findings provide a comprehensive framework for understanding substrate specificity and catalysis in isophthalate dihydrodiol dehydrogenases.IMPORTANCEIsophthalate is a recalcitrant aromatic compound linked to the environmental release of phthalate-based plastics and plasticizers. However, the microbial degradation of isophthalate is relatively less known in comparison to other phthalate isomers. Efficient bacterial utilization of isophthalate requires a coordinated pathway in which the <i>cis</i>-dihydrodiol dehydrogenase IphB converts intermediates into protocatechuate, a central carbon metabolism intermediate. Despite its importance, the structural basis of this transition has remained unclear. Here, we provide a comprehensive structural and biochemical investigation of isophthalate dihydrodiol dehydrogenase (IphB_KF1), revealing the structural basis for cofactor binding, active-site architecture, and conformational dynamics leading to the selective processing of isophthalate-derived substrates. These findings provide a framework for the design of enzymes with improved activity and selectivity for pollutant removal.</p>","PeriodicalId":15107,"journal":{"name":"Journal of Bacteriology","volume":" ","pages":"e0023326"},"PeriodicalIF":3.8,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149238424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Anabaena</i>, a multicellular model for cyanobacterial cell biology and biotechnology.","authors":"Enrique Flores, Ignacio Luque, Rocío López-Igual","doi":"10.1128/jb.00376-26","DOIUrl":"https://doi.org/10.1128/jb.00376-26","url":null,"abstract":"<p><p>Heterocyst-forming cyanobacteria (order Nostocales) are a monophyletic group of organisms that grow as filaments usually made of dozens to hundreds of cells (termed vegetative cells) that can perform oxygenic photosynthesis. Under combined nitrogen deficiency, some cells in the filament differentiate into N₂-fixing heterocysts, which do not produce oxygen and, indeed, keep a microoxic environment appropriate for the expression and functioning of the N₂-fixing enzyme, nitrogenase. Thus, in the diazotrophic filament, oxygenic photosynthesis and N₂ fixation are segregated into two different cell types, vegetative cells and heterocysts, which require intercellular molecular exchange to feed each other with fixed nitrogen and reduced carbon, respectively. The current understanding of heterocyst biology, including regulation of heterocyst differentiation, which also involves intercellular signaling, is the result of studying mainly a few strains of the genus <i>Anabaena</i>. Here, we review the classical studies that established <i>Anabaena</i> as a model for the Nostocales and clarified the basics of N₂ fixation in these organisms. Then, we show how molecular genetics came into the scene and how it was complemented by genomic analysis. This, together with the introduction of modern cell biology approaches, led to a renewed understanding of cellular differentiation and unraveled a system for intercellular communication that is unique in the biological world. In turn, the new accumulated knowledge on <i>Anabaena</i> physiology and genetics makes these organisms an excellent system for the development of new synthetic biology tools that will be crucial for their use in biotechnology.</p>","PeriodicalId":15107,"journal":{"name":"Journal of Bacteriology","volume":" ","pages":"e0037626"},"PeriodicalIF":3.8,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A transcriptional repressor co-regulatory network integrates iron homeostasis and mycobacterial stress tolerance to oxidative stress.","authors":"Khushboo Mehta, Kajal, Harsh Goar, Bhanwar Bamniya, Dibyendu Sarkar","doi":"10.1128/jb.00484-26","DOIUrl":"https://doi.org/10.1128/jb.00484-26","url":null,"abstract":"<p><p>A hallmark of <i>Mycobacterium tuberculosis</i> survival and proliferation within the host is attributable to the effective stress response of the pathogen against hostile environmental conditions. Although controlled iron (Fe) uptake and maintenance of Fe homeostasis are closely associated with intracellular survival of mycobacteria, the underlying mechanism that accounts for the interdependence of mycobacterial Fe regulation and oxidative stress response remains unknown. In this study, we discovered that Fe accumulation connects intra-bacterial redox environment via the <i>phoP</i> locus. Gene expression analyses coupled with genetic, biochemical, and transcriptomic studies uncover a distinct mechanism that utilizes Lsr2 and the virulence regulator PhoP to modulate transcriptional control of the major Fe storage protein-encoding gene <i>bfrB</i>. Remarkably, regulated expression of <i>bfrB</i> determines bacterial tolerance to oxidative stress and its intracellular survival. Although both regulators could independently influence <i>bfrB</i> expression, the most fundamental insights are derived from the inhibition of Lsr2 binding at the <i>bfrB</i> regulatory region of the <i>phoP</i>-KO mutant strain owing to Lsr2-PhoP protein-protein interactions. Building on these results, we proposed a model suggesting how Lsr2-PhoP interaction, or lack thereof, contributes to stress-specific regulation of <i>bfrB</i> expression. Collectively, these results uncover a key mechanism integrating Fe accumulation to oxidative stress response, an essential pathogenic determinant of <i>M. tuberculosis</i>.IMPORTANCEWhile the availability of Fe remains essential for <i>Mycobacterium tuberculosis</i> infection and replication of the pathogen in human macrophages, Fe may be harmful as it catalyzes the generation of toxic reactive oxygen species from products of aerobic respiration to induce oxidative stress. Although interdependence of mycobacterial Fe regulation and oxidative stress response has been reported, the mechanism connecting Fe acquisition and oxidative stress response is yet to be fully understood. Results reported in this study identify and elaborate on a new mechanism of regulation of expression of the major mycobacterial Fe storage protein, which determines bacterial tolerance to oxidative stress and impacts intracellular survival of the pathogen. We demonstrate that the virulence-associated <i>phoP</i> locus controls Fe accumulation and contributes to the intra-bacterial redox environment. The results uncover a distinctly different transcriptional control mechanism of the major Fe storage protein requiring a co-repressor-dependent regulatory circuit, including nucleoid-associated protein Lsr2 and the virulence regulator PhoP. Together, these results unveil a unique mechanism of stress-specific gene expression, which integrates Fe homeostasis to oxidative stress response, an essential pathogenic determinant of <i>M. tuberculosis</i>.</p>","PeriodicalId":15107,"journal":{"name":"Journal of Bacteriology","volume":" ","pages":"e0048426"},"PeriodicalIF":3.8,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}