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1. Enzyme-constrained metabolic model of Treponema pallidum identified glycerol-3-phosphate dehydrogenase as an alternate electron sink

   https://doi.org/10.1128/msystems.01555-24  

   Shahreen, Nabia; Chowdhury, Niaz Bahar; Stone, Edward; Knobbe, Elle; Saha, Rajib (May 2025, mSystems)

   Zhang, Ying (Ed.)

   ABSTRACT Treponema pallidum, the causative agent of syphilis, poses a significant global health threat. Its strict reliance on host-derived nutrients and difficulties inin vitrocultivation have impeded detailed metabolic characterization. In this study, we present iTP251, the first genome-scale metabolic model ofT. pallidum, reconstructed and extensively curated to capture its unique metabolic features. These refinements included the curation of key reactions such as pyrophosphate-dependent phosphorylation and pathways for nucleotide synthesis, amino acid synthesis, and cofactor metabolism. The model demonstrated high predictive accuracy, validated by a MEMOTE score of 92%. To further enhance its predictive capabilities, we developed ec-iTP251, an enzyme-constrained version of iTP251, incorporating enzyme turnover rate and molecular weight information for all reactions having gene-protein-reaction associations. Ec-iTP251 provides detailed insights into protein allocation across carbon sources, showing strong agreement with proteomics data (Pearson’s correlation of 0.88) in the central carbon pathway. Moreover, the thermodynamic analysis revealed that lactate uptake serves as an additional ATP-generating strategy to utilize unused proteomes, albeit at the cost of reducing the driving force of the central carbon pathway by 27%. Subsequent analysis identified glycerol-3-phosphate dehydrogenase as an alternative electron sink, compensating for the absence of a conventional electron transport chain while maintaining cellular redox balance. These findings highlightT. pallidum’s metabolic adaptations for survival and redox balance in nutrient-limited, extracellular host environments, providing a foundation for future research into its unique bioenergetics. IMPORTANCEThis study advances our understanding ofTreponema pallidum, the syphilis-causing pathogen, through the reconstruction of iTP251, the first genome-scale metabolic model for this organism, and its enzyme-constrained version, ec-iTP251. The work addresses the challenges of studyingT. pallidum, an extracellular, host-adapted pathogen, due to its strict dependence on host-derived nutrients and challenges inin vitrocultivation. Validated with strong agreement to proteomics data, the model demonstrates high predictive reliability. Key insights include unique metabolic adaptations such as lactate uptake for ATP production and alternative redox-balancing mechanisms. These findings provide a robust framework for future studies aimed at unraveling the pathogen's survival strategies and identifying potential metabolic vulnerabilities. 

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2. Ecology of inorganic sulfur auxiliary metabolism in widespread bacteriophages

   https://doi.org/10.1038/s41467-021-23698-5  

   Kieft, Kristopher; Zhou, Zhichao; Anderson, Rika E.; Buchan, Alison; Campbell, Barbara J.; Hallam, Steven J.; Hess, Matthias; Sullivan, Matthew B.; Walsh, David A.; Roux, Simon; et al (December 2021, Nature Communications)

   null (Ed.)

   Abstract Microbial sulfur metabolism contributes to biogeochemical cycling on global scales. Sulfur metabolizing microbes are infected by phages that can encode auxiliary metabolic genes (AMGs) to alter sulfur metabolism within host cells but remain poorly characterized. Here we identified 191 phages derived from twelve environments that encoded 227 AMGs for oxidation of sulfur and thiosulfate ( dsrA , dsrC/tusE , soxC , soxD and soxYZ ). Evidence for retention of AMGs during niche-differentiation of diverse phage populations provided evidence that auxiliary metabolism imparts measurable fitness benefits to phages with ramifications for ecosystem biogeochemistry. Gene abundance and expression profiles of AMGs suggested significant contributions by phages to sulfur and thiosulfate oxidation in freshwater lakes and oceans, and a sensitive response to changing sulfur concentrations in hydrothermal environments. Overall, our study provides fundamental insights on the distribution, diversity, and ecology of phage auxiliary metabolism associated with sulfur and reinforces the necessity of incorporating viral contributions into biogeochemical configurations. 

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3. Distinct polyamine effects on Candida albicans morphogenesis identify spermidine as a key regulator

   https://doi.org/10.1128/spectrum.00833-26  

   Pathirana, Ruvini U; Camargo, Minelly I; Vela, Geysira G; Kadosh, David (September 2026, Microbiology Spectrum)

   Kovacs, Renato (Ed.)

   ABSTRACT Polyamines play essential and multifaceted roles in all organisms. However, their unique functions in fungal cell differentiation provide an opportunity to identify novel antifungal targets, as inhibition of essential metabolic pathways represents a promising therapeutic strategy. In this study, we characterized two putative regulators of the polyamine biosynthesis pathway in the major human fungal pathogenCandida albicans, identified based on their homology toSaccharomyces cerevisiae SPE1andSPE2, which encode ornithine decarboxylase andS-adenosylmethionine decarboxylase, respectively. We generated single and double gene deletion strains for CaSPE1and CaSPE2and found that disruption of these genes severely impaired yeast cell growth due to disturbed polyamine homeostasis. This dysregulation was associated with pronounced cell vacuolar enlargement, indicating that cellular stress is linked to polyamine imbalance. Filamentation analyses revealed that polyamine-induced morphogenesis by spermine and spermidine is growth medium-dependent, likely reflecting differences in the bioavailability of different types of polyamines. Among the polyamines tested, spermine acted synergistically with glucose to promote filamentation in minimal medium. Collectively, our findings demonstrate that polyamines mediate a finely tuned balance between yeast cell proliferation and filamentous growth inC. albicans. Notably, spermidine directly regulates polyamine homeostasis to govern cell growth and filamentation, and spermine appears to be the primary polyamine driving filamentation, potentially through a dual signaling mechanism that integrates metabolic status and morphogenetic regulation. IMPORTANCEMetabolic plasticity is a critical determinant of microbial commensalism and pathogenicity, shaped by the evolutionary pressure that drives niche-specific adaptations. These processes are not well understood in a species-specific context across diverse morphogenetic programs that govern fungal adaptations. As a major dimorphic human fungal pathogen,Candida albicansfinely tunes its metabolic pathways to support its growth and virulence properties, including morphogenesis. Here, we investigated one such understudied pathway: polyamine metabolism under distinct growth conditions. Building upon previous studies on fungal polyamine biology, we demonstrated that polyamine homeostasis influences growth, cell morphology, and filamentation inC. albicans. This study expands our understanding of how diverse polyamines shapeC. albicansphysiology by providing insight into the dual roles of polyamines as nutrients and signaling molecules. These findings illustrate the complex relationship between polyamine metabolism and morphogenesis inC. albicanswhile identifying polyamine metabolism as a pathway of continued interest for antifungal target discovery. 

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4. Acclimation temperature influences phage susceptibility in a toxin-producing strain of Microcystis aeruginosa

   https://doi.org/10.1128/spectrum.03379-25  

   Hambrick, Kennedi M; Smith, Laura E; Martin, Robbie M; Wei, Bofan; Dey, Raunak; Boyer, Gregory L; Weitz, Joshua S; Talmy, David; Wilhelm, Steven W; Zinser, Erik R (June 2026, Microbiology Spectrum)

   Gonzalez, Victor (Ed.)

   ABSTRACT Microcystis aeruginosais a freshwater cyanobacterium known for its role in the formation of harmful algal blooms. However, less well characterized are the host-phage interactions that occur in these toxic blooms. Here, we describe the relationship between a microcystin-producing strain ofM. aeruginosa,NIES-298, and a lytic bacteriophage Ma-LMM01. In this study, we explored how host pre-acclimation to different temperature conditions influenced sensitivity to subsequent infection by Ma-LMM01. We focused on 19°C, a cooler temperature often associated with microcystin-producing blooms in spring/early summer, and 26°C, a warmer temperature often associated with non-microcystin-producing blooms of late summer.M. aeruginosacultures pre-acclimated to 26°C were completely lysed whether infection occurred at 26°C or 19°C. In contrast, 19°C-acclimatedM. aeruginosagrew and resisted infection regardless of infection temperature. We next formulated a mathematical model to investigate the key parameters driving these temperature dynamics. Our modeling suggested both 19°C- and 26°C-acclimated hosts contain resistant subpopulations of comparable abundance but with different degrees of resistance. Specifically, we found the 19°C-acclimated host subpopulation was substantially more resistant to phage infection than the 26°C-acclimated host subpopulation, which was only partially resistant. Overall, our observations demonstrate thatM. aeruginosaNIES-298 acclimation to 19°C played a role in the development of resistance to cyanophage Ma-LMM01. These findings suggest new directions to explore the link between physiological changes and infection outcomes for microcystin-producing cyanobacteria in changing environments.IMPORTANCEHarmful cyanobacterial blooms frequently develop in aquatic systems, causing significant ecological and commercial impact, motivating research into factors influencing bloom formation, persistence, and toxicity. Prior studies identified several contributors to the “life cycle” of a toxic bloom, including abiotic influences, community structure, and host-viral interactions. This paper explores two of these factors, temperature and viral-host interactions, on the growth and survival ofMicrocystis aeruginosaNIES-298. We report the first observation that the acclimation temperature ofM. aeruginosainfluences phage susceptibility, and through mathematical modeling, explore resistant subpopulation dynamics. We observed that cells acclimated to cold temperatures, such as those experienced in spring/early summer, were resistant to phage, while those acclimated to warmer temperatures, such as those experienced in late summer, were not. This work contributes to the fields of freshwater ecology and microbial physiology by advancing our understanding of the interplay between host-phage interactions and abiotic influences in toxic algal bloom formation. 

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5. Vibrio parahaemolyticus quorum sensing controls phage VP882 transmission

   https://doi.org/10.1128/mbio.00737-26  

   Sargen, Molly R; Bassler, Bonnie L (May 2026, mBio)

   Penades, José (Ed.)

   ABSTRACT Quorum sensing is a cell-to-cell communication process bacteria use to orchestrate collective behaviors. Quorum sensing involves the production, release, and detection of extracellular signal molecules called autoinducers. Some temperate phages can monitor bacterial autoinducers, enabling them to track the abundance of potential host cells in the vicinity. Quorum-sensing-responsive phages can preferentially launch the transition from lysogeny to lytic replication at high cell density, presumably maximizing transmission. Once the phage lytic program is enacted, if nearby host cells are already lysogens, infections initiated by released virions could be nonproductive due to homoimmunity or superinfection exclusion mechanisms, posing a conundrum for temperate phages, including those that surveil quorum-sensing autoinducers. Here, we define host and phage components that influence the transmission of the first-discovered quorum-sensing-responsive phage, phage VP882, in populations of its host,Vibrio parahaemolyticus. We show that phage VP882 uses the K-antigen of serotype O3:K6 as its receptor. We demonstrate that host cells can prevent phage access to the O3:K6 K-antigen via quorum-sensing control of the export of polysaccharides that shield the K-antigen from the phage at high cell density. We discover that phage VP882 can superinfect and superlysogenizeV. parahaemolyticus, overcoming the challenge of detecting whether or not potential hosts are lysogens. Following superlysogenization, recombination of the resident and newly infecting phage genomes can occur, possibly promoting phage VP882 genome diversification. IMPORTANCEA longstanding mystery is how temperate phages optimally time the launch of their lytic cascades to maximize spread. Quorum-sensing-responsive phages can preferentially execute their lytic replication programs at high host cell density, which in principle should foster transmission. However, if nearby host cells are already lysogens, infections initiated by released virions could be nonproductive due to homoimmunity or superinfection exclusion. We define host and phage components influencing the transmission of the quorum-sensing-responsive phage VP882 inVibrio parahaemolyticuspopulations. Phage VP882 uses the O3:K6 K-antigen as its receptor. Host cells prevent phage infection via quorum-sensing-controlled export of polysaccharides that shield the K-antigen at high cell density. We discover that phage VP882 can superinfect and superlysogenizeV. parahaemolyticus, overcoming the challenge of detecting whether or not potential hosts are lysogens. These findings reveal how phages can capitalize on interception of host quorum-sensing cues to maximize their reproductive success. 

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