Pub Date : 2026-05-01Epub Date: 2026-01-19DOI: 10.1016/j.micres.2026.128454
Junnan Huang , Xuejuan Xia , Jing Lu , Xuanyu Chen , Keyao Ye , Jia Yu , Zhuosi Li , Yue Ma , Xiaojie Qin , Yangtai Liu , Xiang Wang , Hai Chi , Guannan Li , Chang Liu , Qingli Dong
Listeria monocytogenes (LM) is a significant foodborne pathogen with considerable resilience in diverse environments. Following ingestion via contaminated food, LM can breach the intestinal barrier and infect target organs, causing systemic infection. This breach represents a critical step in its pathogenesis. The gut microbiota, a key component of intestinal defense, can restrict the colonization and invasion of the pathogen through mechanisms such as nutrient competition and bacteriocin production. In response, LM has evolved counterstrategies to enhance its survival and invasiveness in the gut environment. Furthermore, the efficacy of the gut microbiota in resisting LM is influenced by multiple factors, such as population differences and dietary habits, leading to variations in susceptibility to infection among individuals. Currently, antibiotic therapy for listeriosis faces limitations, highlighting the need for alternative control and therapeutic strategies. This review systematically summarizes the mechanisms by which the gut microbiota resists LM, the adaptive strategies of the pathogen, and the factors influencing this interaction. It also discusses current microbiota-based preventive and therapeutic approaches, aiming to provide a theoretical foundation for future research.
{"title":"Protective role of the gut microbiota against Listeria monocytogenes: From colonization resistance to therapeutic approaches","authors":"Junnan Huang , Xuejuan Xia , Jing Lu , Xuanyu Chen , Keyao Ye , Jia Yu , Zhuosi Li , Yue Ma , Xiaojie Qin , Yangtai Liu , Xiang Wang , Hai Chi , Guannan Li , Chang Liu , Qingli Dong","doi":"10.1016/j.micres.2026.128454","DOIUrl":"10.1016/j.micres.2026.128454","url":null,"abstract":"<div><div><em>Listeria monocytogenes</em> (LM) is a significant foodborne pathogen with considerable resilience in diverse environments. Following ingestion via contaminated food, LM can breach the intestinal barrier and infect target organs, causing systemic infection. This breach represents a critical step in its pathogenesis. The gut microbiota, a key component of intestinal defense, can restrict the colonization and invasion of the pathogen through mechanisms such as nutrient competition and bacteriocin production. In response, LM has evolved counterstrategies to enhance its survival and invasiveness in the gut environment. Furthermore, the efficacy of the gut microbiota in resisting LM is influenced by multiple factors, such as population differences and dietary habits, leading to variations in susceptibility to infection among individuals. Currently, antibiotic therapy for listeriosis faces limitations, highlighting the need for alternative control and therapeutic strategies. This review systematically summarizes the mechanisms by which the gut microbiota resists LM, the adaptive strategies of the pathogen, and the factors influencing this interaction. It also discusses current microbiota-based preventive and therapeutic approaches, aiming to provide a theoretical foundation for future research.</div></div>","PeriodicalId":18564,"journal":{"name":"Microbiological research","volume":"306 ","pages":"Article 128454"},"PeriodicalIF":6.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To uncover novel genetic factors required for Listeria monocytogenes cell infection, we developed an automated high-throughput microscopy screening pipeline that integrates GFP-expressing bacteria with machine learning-based image analysis. Using this approach, we screened a mariner transposon library comprising 4224 L. monocytogenes EGDe mutants and identified 58 with significantly reduced numbers of intracellular bacteria. Sequencing revealed 24 unique insertion sites corresponding to 14 genes, including previously known virulence factors and nine novel candidates not previously implicated in cell infection. These genes encode the protease chaperone ClpX, the ferric uptake regulator Fur, the sensor histidine kinase LisK, the peptide chain release factor 2 PrfB, proteins involved in proline and purine biosynthesis (ProAB, PurAB), and Lmo2217, a protein of unknown function. Among these, the targeted deletion of the adenylosuccinate synthetase gene, purA, resulted in impaired growth in minimal medium, severely reduced proliferation in epithelial and macrophage cell lines, and attenuated virulence in mice. Unexpectedly, PurA was also essential for bacterial internalization into cells. Supplementation with AMP or adenine, but not ATP, rescued the invasion capacity of the ΔpurA mutant. Mechanistically, purA deletion induced a reduction in the levels of surface-associated GAPDH, a putative plasminogen-binding protein, likely contributing to the observed invasion defect. Overall, these findings highlight the power of automated high-throughput microscopy screening to dissect host–pathogen interactions, identify novel L. monocytogenes genes required for cell infection, and uncover an unexpected role for PurA in maintaining GAPDH surface localization and promoting bacterial entry into host cells.
{"title":"Automated high-throughput microscopy screening unveiled new Listeria monocytogenes genes involved in cell infection","authors":"Ângela Alves , Diana Meireles , Chiara Suriano , Ricardo Monteiro , Rute Oliveira , Beatriz G. Bernardes , Sandra Sousa , Rita Pombinho , Didier Cabanes","doi":"10.1016/j.micres.2026.128442","DOIUrl":"10.1016/j.micres.2026.128442","url":null,"abstract":"<div><div>To uncover novel genetic factors required for <em>Listeria monocytogenes</em> cell infection, we developed an automated high-throughput microscopy screening pipeline that integrates GFP-expressing <em>bacteria</em> with machine learning-based image analysis. Using this approach, we screened a mariner transposon library comprising 4224 <em>L. monocytogenes</em> EGDe mutants and identified 58 with significantly reduced numbers of intracellular bacteria. Sequencing revealed 24 unique insertion sites corresponding to 14 genes, including previously known virulence factors and nine novel candidates not previously implicated in cell infection. These genes encode the protease chaperone ClpX, the ferric uptake regulator Fur, the sensor histidine kinase LisK, the peptide chain release factor 2 PrfB, proteins involved in proline and purine biosynthesis (ProAB, PurAB), and Lmo2217, a protein of unknown function. Among these, the targeted deletion of the adenylosuccinate synthetase gene, <em>purA</em>, resulted in impaired growth in minimal medium, severely reduced proliferation in epithelial and macrophage cell lines, and attenuated virulence in mice. Unexpectedly, PurA was also essential for bacterial internalization into cells. Supplementation with AMP or adenine, but not ATP, rescued the invasion capacity of the Δ<em>purA</em> mutant. Mechanistically, <em>purA</em> deletion induced a reduction in the levels of surface-associated GAPDH, a putative plasminogen-binding protein, likely contributing to the observed invasion defect. Overall, these findings highlight the power of automated high-throughput microscopy screening to dissect host–pathogen interactions, identify novel <em>L. monocytogenes</em> genes required for cell infection, and uncover an unexpected role for PurA in maintaining GAPDH surface localization and promoting bacterial entry into host cells.</div></div>","PeriodicalId":18564,"journal":{"name":"Microbiological research","volume":"306 ","pages":"Article 128442"},"PeriodicalIF":6.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145981354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-05-01Epub Date: 2026-01-15DOI: 10.1016/j.micres.2026.128451
Jingwen Bai, Jinjin Zheng, Chi Wei, Bin Yu, Jingwen Sun, Ziyang Feng, Yu Yang
The global spread of methicillin-resistant Staphylococcus aureus (MRSA) urgently demands novel therapeutic strategies. This study demonstrates that honokiol (HNK), a natural biphenolic compound, is a potent and broad-spectrum agent against MRSA, including clinical isolates. HNK exhibited rapid bactericidal activity, effectively disrupted biofilms, and in a murine abscess model, significantly promoted wound healing while reducing pro-inflammatory cytokines, with excellent biocompatibility. Through an integrated multi-omics, biochemical, and biophysical approach, we identified pyruvate kinase (PYK), the terminal enzyme of glycolysis, as the primary cellular target. Remarkably, HNK employs a dual-targeting strategy, concurrently inhibiting PYK enzyme activity and downregulating pyk gene transcription. Molecular docking, dynamics simulations, and computational mutagenesis delineated the precise binding mode and validated key interaction residues. This concerted attack triggers a catastrophic metabolic cascade severe obstruction of glycolytic flux, impairment of the TCA cycle, profound depletion of ATP/NADH, and oxidative stress ultimately leading to bacterial death and virulence attenuation. Our findings not only elucidate a novel antibacterial mechanism centered on the simultaneous transcriptional and functional inhibition of a metabolic hub but also provide a structural basis for drug design, positioning HNK as a valuable lead compound against multidrug-resistant staphylococcal infections. The definitive genetic validation of PYK as the essential target remains the critical next step to advance this therapeutic strategy.
{"title":"Natural product honokiol exerts anti-methicillin resistant Staphylococcus aureus infection activity by targeting pyruvate kinase to inhibit glucose metabolism","authors":"Jingwen Bai, Jinjin Zheng, Chi Wei, Bin Yu, Jingwen Sun, Ziyang Feng, Yu Yang","doi":"10.1016/j.micres.2026.128451","DOIUrl":"10.1016/j.micres.2026.128451","url":null,"abstract":"<div><div>The global spread of methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) urgently demands novel therapeutic strategies. This study demonstrates that honokiol (HNK), a natural biphenolic compound, is a potent and broad-spectrum agent against MRSA, including clinical isolates. HNK exhibited rapid bactericidal activity, effectively disrupted biofilms, and in a murine abscess model, significantly promoted wound healing while reducing pro-inflammatory cytokines, with excellent biocompatibility. Through an integrated multi-omics, biochemical, and biophysical approach, we identified pyruvate kinase (PYK), the terminal enzyme of glycolysis, as the primary cellular target. Remarkably, HNK employs a dual-targeting strategy, concurrently inhibiting PYK enzyme activity and downregulating <em>pyk</em> gene transcription. Molecular docking, dynamics simulations, and computational mutagenesis delineated the precise binding mode and validated key interaction residues. This concerted attack triggers a catastrophic metabolic cascade severe obstruction of glycolytic flux, impairment of the TCA cycle, profound depletion of ATP/NADH, and oxidative stress ultimately leading to bacterial death and virulence attenuation. Our findings not only elucidate a novel antibacterial mechanism centered on the simultaneous transcriptional and functional inhibition of a metabolic hub but also provide a structural basis for drug design, positioning HNK as a valuable lead compound against multidrug-resistant staphylococcal infections. The definitive genetic validation of PYK as the essential target remains the critical next step to advance this therapeutic strategy.</div></div>","PeriodicalId":18564,"journal":{"name":"Microbiological research","volume":"306 ","pages":"Article 128451"},"PeriodicalIF":6.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145981352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2025-12-19DOI: 10.1016/j.micres.2025.128428
Marta Pulido-Sánchez , Elisa Montero-Beltrán , Aroa López-Sánchez , Fernando Govantes
Pseudomonas putida biofilm growth is associated to nutrient-sufficient conditions and biofilm dispersal is induced by nutrient starvation, signaled by the stringent response-associated nucleotide alarmone (p)ppGpp. We have used transcriptomic analysis to show that (p)ppGpp regulates the hsbAR-hptB gene cluster, encoding components of a phosphorelay pathway and an anti-σ factor antagonist, and cfcR, encoding a response regulator with diguanylate cyclase (DGC) activity. Transcription of hsbAR-hptB and cfcR is RpoS-dependent and induced by stationary phase and the stringent response. A ∆hsbA mutant resumed biofilm formation after dispersal in late stationary phase and displayed increased pellicle formation at the medium-air interphase and Congo Red adsorption. All these phenotypes were traced down to increased c-di-GMP levels in stationary phase, dependent on the activity of CfcR and its cognate sensor kinase, CfcA. HsbA was reversibly phosphorylated by the combined action of HptB and HsbR. HsbA phosphorylation conditioned its interaction with CfcR and CfcA and the subcellular distribution of the three proteins. In spite of this, HsbA retained its ability to prevent biofilm formation regardless of its phosphorylation state. Our results support a model in which HsbA forms a complex with CfcR to inhibit its DGC activity regardless of its phosphorylation state. Upon HsbA dephosphorylation, this complex is recruited to the cell membrane by CfcA to strengthen the inhibitory effect. While this pathway contributes to biofilm dispersal by denying de novo c-di-GMP synthesis during nutrient starvation, it may also enable quick restoration of the biofilm phenotype to colonize new sites or during biofilm maturation.
{"title":"HsbA represses stationary phase biofilm formation in Pseudomonas putida","authors":"Marta Pulido-Sánchez , Elisa Montero-Beltrán , Aroa López-Sánchez , Fernando Govantes","doi":"10.1016/j.micres.2025.128428","DOIUrl":"10.1016/j.micres.2025.128428","url":null,"abstract":"<div><div><em>Pseudomonas putida</em> biofilm growth is associated to nutrient-sufficient conditions and biofilm dispersal is induced by nutrient starvation, signaled by the stringent response-associated nucleotide alarmone (p)ppGpp. We have used transcriptomic analysis to show that (p)ppGpp regulates the <em>hsbAR-hptB</em> gene cluster, encoding components of a phosphorelay pathway and an anti-σ factor antagonist, and <em>cfcR</em>, encoding a response regulator with diguanylate cyclase (DGC) activity. Transcription of <em>hsbAR-hptB</em> and <em>cfcR</em> is RpoS-dependent and induced by stationary phase and the stringent response. A ∆<em>hsbA</em> mutant resumed biofilm formation after dispersal in late stationary phase and displayed increased pellicle formation at the medium-air interphase and Congo Red adsorption. All these phenotypes were traced down to increased c-di-GMP levels in stationary phase, dependent on the activity of CfcR and its cognate sensor kinase, CfcA. HsbA was reversibly phosphorylated by the combined action of HptB and HsbR. HsbA phosphorylation conditioned its interaction with CfcR and CfcA and the subcellular distribution of the three proteins. In spite of this, HsbA retained its ability to prevent biofilm formation regardless of its phosphorylation state. Our results support a model in which HsbA forms a complex with CfcR to inhibit its DGC activity regardless of its phosphorylation state. Upon HsbA dephosphorylation, this complex is recruited to the cell membrane by CfcA to strengthen the inhibitory effect. While this pathway contributes to biofilm dispersal by denying <em>de novo</em> c-di-GMP synthesis during nutrient starvation, it may also enable quick restoration of the biofilm phenotype to colonize new sites or during biofilm maturation.</div></div>","PeriodicalId":18564,"journal":{"name":"Microbiological research","volume":"305 ","pages":"Article 128428"},"PeriodicalIF":6.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145789522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bacterial infections pose a significant threat to host cells by inducing DNA damage, potentially leading to chromosomal instability, cell cycle arrest, apoptosis, or even cancer. Pseudomonas aeruginosa (P. aeruginosa) infection-induced DNA double-strand breaks (DSBs) activates DNA damage response (DDR) to facilitate repair. However, the mechanisms linking P. aeruginosa infection and host DNA repair remain unclear. Here, we demonstrate that DSBs-induced by P. aeruginosa in lung epithelial cells promote Tip60 activation and stabilization, which help counteract DNA damage. However, diminished Tip60 activation and reduced protein levels during the post-infection recovery phase exacerbate DNA damage. Mechanistically, elevated Tip60 levels during infection are associated with suppressed K33- and K48-linked ubiquitination, whereas the decline of Tip60 during recovery coincides with enhanced K33- and K48-linked ubiquitination. These specific ubiquitination modifications promote proteasomal degradation of Tip60, thereby reducing its stability. Supporting this, we observed that wild-type Tip60 undergoes markedly less K33- and K48-linked ubiquitination than its histone acetyltransferase (HAT) activity-deficient mutant. Notably, we identify the E3 ubiquitin ligase TRIM37 as a positive regulator of Tip60 stability, largely independent of its E3 ligase activity. Silencing TRIM37 enhances K33- and K48-linked ubiquitination and accelerates Tip60 degradation, thereby exacerbating DNA damage during both infection and recovery. TRIM37 binds to the C-terminal MYST domain of Tip60, with this interaction strengthened during infection but weakened upon recovery. This dynamic regulation arises because TRIM37 preferentially associates with the activated form of Tip60. Collectively, our findings identify the TRIM37-Tip60 axis as a critical regulator of host DDR in response to P. aeruginosa infection, offering new insights into infection-associated DDR and therapeutic strategies.
{"title":"Dynamic regulation of K33- and K48-linked ubiquitination of Tip60 by TRIM37 orchestrates host DNA damage response during Pseudomonas aeruginosa infection and recovery","authors":"Hua Yu , Xingmin Wang , Junzhi Xiong, Xiaomei He, Caifeng Ma, Qilin Wang, Rongrong Chen, Yuanyuan Li, Qian Dai, Qian Min, Jianyun Zhou, Kebin Zhang","doi":"10.1016/j.micres.2025.128414","DOIUrl":"10.1016/j.micres.2025.128414","url":null,"abstract":"<div><div>Bacterial infections pose a significant threat to host cells by inducing DNA damage, potentially leading to chromosomal instability, cell cycle arrest, apoptosis, or even cancer. <em>Pseudomonas aeruginosa</em> (<em>P. aeruginosa</em>) infection-induced DNA double-strand breaks (DSBs) activates DNA damage response (DDR) to facilitate repair. However, the mechanisms linking <em>P. aeruginosa</em> infection and host DNA repair remain unclear. Here, we demonstrate that DSBs-induced by <em>P. aeruginosa</em> in lung epithelial cells promote Tip60 activation and stabilization, which help counteract DNA damage. However, diminished Tip60 activation and reduced protein levels during the post-infection recovery phase exacerbate DNA damage. Mechanistically, elevated Tip60 levels during infection are associated with suppressed K33- and K48-linked ubiquitination, whereas the decline of Tip60 during recovery coincides with enhanced K33- and K48-linked ubiquitination. These specific ubiquitination modifications promote proteasomal degradation of Tip60, thereby reducing its stability. Supporting this, we observed that wild-type Tip60 undergoes markedly less K33- and K48-linked ubiquitination than its histone acetyltransferase (HAT) activity-deficient mutant. Notably, we identify the E3 ubiquitin ligase TRIM37 as a positive regulator of Tip60 stability, largely independent of its E3 ligase activity. Silencing TRIM37 enhances K33- and K48-linked ubiquitination and accelerates Tip60 degradation, thereby exacerbating DNA damage during both infection and recovery. TRIM37 binds to the C-terminal MYST domain of Tip60, with this interaction strengthened during infection but weakened upon recovery. This dynamic regulation arises because TRIM37 preferentially associates with the activated form of Tip60. Collectively, our findings identify the TRIM37-Tip60 axis as a critical regulator of host DDR in response to <em>P. aeruginosa</em> infection, offering new insights into infection-associated DDR and therapeutic strategies.</div></div>","PeriodicalId":18564,"journal":{"name":"Microbiological research","volume":"305 ","pages":"Article 128414"},"PeriodicalIF":6.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145828015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2025-12-16DOI: 10.1016/j.micres.2025.128417
Xiao Yu , Jinbei Zhang , Xiangmei Li , Guyu Li , Xiaoxiao Lu , Yinghan Shi , Wei Lin , Xiuli Wang , Weihua Zhang , Yigang Tong , Mengzhe Li , Lixin Xie , Mengying Yao
Pseudomonas aeruginosa is a major opportunistic pathogen implicated in a wide range of infections, including chronic respiratory infections, burn wound infections, urinary tract infections, and device-associated infections. Its intrinsic and acquired resistance mechanisms, particularly its capacity for biofilm formation, pose serious challenges to conventional antibiotic therapy. With the continued rise of multidrug-resistant and pan-drug-resistant strains, the need for alternative therapeutic strategies has become increasingly urgent. Phages, viruses that specifically recognize and lyse bacteria, have shown unique advantages in combating antibiotic-resistant infections. This review systematically summarizes recent advances in the application of phage therapy for P. aeruginosa infections, covering in vitro bactericidal activity, biofilm degradation, and synergistic interactions with antibiotics. We further discuss evidence from animal models, including therapeutic efficacy, immunomodulatory effects, and pharmacokinetics. Emphasis is placed on clinical use cases, including different routes of administration, symptom relief, biomarker modulation, pathogen clearance rates, and adverse events. Typical case reports and early-phase clinical trials support the safety and efficacy of phage therapy. Nevertheless, translational barriers persist, such as the need for precise host matching, risks of immune neutralization, and the lack of standardized regulatory frameworks and Good Manufacturing Practice (GMP)-grade production systems. The rapid development of engineered phages and individualized therapeutic approaches offers a feasible path forward. In conclusion, phage therapy holds significant promise for the treatment of drug-resistant P. aeruginosa infections, and future efforts should focus on establishing standardized systems, conducting multicenter clinical studies, and leveraging synthetic biology to accelerate its translation from bench to bedside.
{"title":"A review of phage therapy for drug-resistant Pseudomonas aeruginosa infections","authors":"Xiao Yu , Jinbei Zhang , Xiangmei Li , Guyu Li , Xiaoxiao Lu , Yinghan Shi , Wei Lin , Xiuli Wang , Weihua Zhang , Yigang Tong , Mengzhe Li , Lixin Xie , Mengying Yao","doi":"10.1016/j.micres.2025.128417","DOIUrl":"10.1016/j.micres.2025.128417","url":null,"abstract":"<div><div><em>Pseudomonas aeruginosa</em> is a major opportunistic pathogen implicated in a wide range of infections, including chronic respiratory infections, burn wound infections, urinary tract infections, and device-associated infections. Its intrinsic and acquired resistance mechanisms, particularly its capacity for biofilm formation, pose serious challenges to conventional antibiotic therapy. With the continued rise of multidrug-resistant and pan-drug-resistant strains, the need for alternative therapeutic strategies has become increasingly urgent. Phages, viruses that specifically recognize and lyse bacteria, have shown unique advantages in combating antibiotic-resistant infections. This review systematically summarizes recent advances in the application of phage therapy for <em>P. aeruginosa</em> infections, covering <em>in vitro</em> bactericidal activity, biofilm degradation, and synergistic interactions with antibiotics. We further discuss evidence from animal models, including therapeutic efficacy, immunomodulatory effects, and pharmacokinetics. Emphasis is placed on clinical use cases, including different routes of administration, symptom relief, biomarker modulation, pathogen clearance rates, and adverse events. Typical case reports and early-phase clinical trials support the safety and efficacy of phage therapy. Nevertheless, translational barriers persist, such as the need for precise host matching, risks of immune neutralization, and the lack of standardized regulatory frameworks and Good Manufacturing Practice (GMP)-grade production systems. The rapid development of engineered phages and individualized therapeutic approaches offers a feasible path forward. In conclusion, phage therapy holds significant promise for the treatment of drug-resistant <em>P. aeruginosa</em> infections, and future efforts should focus on establishing standardized systems, conducting multicenter clinical studies, and leveraging synthetic biology to accelerate its translation from bench to bedside.</div></div>","PeriodicalId":18564,"journal":{"name":"Microbiological research","volume":"305 ","pages":"Article 128417"},"PeriodicalIF":6.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2025-12-19DOI: 10.1016/j.micres.2025.128429
Luis Fernando Montelongo-Martínez , Abigail González-Valdez , Gloria Soberón-Chávez , Miguel Cocotl-Yañez
Pyocyanin is the primary phenazine produced by Pseudomonas aeruginosa, which possesses redox activity. This compound contributes to its virulence by generating reactive oxygen species and inducing oxidative stress in prokaryotic and eukaryotic cells. P. aeruginosa is able to resist high concentrations of pyocyanin despite its toxicity. In this work, we employed P. aeruginosa ID4365 and PAO1 rsmA mutants, which produce 276.2 μM and 6.9 μM of pyocyanin, respectively, to conduct a proteomic analysis in order to identify proteins involved in the protective response against this phenazine. We found that inactivation of rsmA in ID4365 altered the levels of 474 proteins, including those related to the oxidative stress response, efflux pumps, and chaperones. While in PAO1, rsmA inactivation affected the levels of 177 proteins, and only MexH, which is part of the MexGHI-OpmD efflux pump involved in exporting pyocyanin, was identified as a protein related to the protective response. We further determined whether RsmA controls the pyocyanin protective response in ID4365 and found that expression of genes encoding OxyR, SoxR, and Fur, which are essential for oxidative stress defense and iron homeostasis, were negatively regulated by RsmA. Moreover, we demonstrate that RsmA negatively controls the GroESL chaperone system, suggesting its role in alleviating pyocyanin-induced proteotoxic stress. Our findings indicate that the protective response against pyocyanin is more pronounced in ID4365 compared to the PAO1 strain when rsmA is deleted. Thus, RsmA plays a crucial role in this strain by regulating the response to prevent damage caused by pyocyanin overproduction.
{"title":"The post-transcriptional regulator RsmA mediates the protective response against pyocyanin overproduction in Pseudomonas aeruginosa, as revealed by a proteomic approach","authors":"Luis Fernando Montelongo-Martínez , Abigail González-Valdez , Gloria Soberón-Chávez , Miguel Cocotl-Yañez","doi":"10.1016/j.micres.2025.128429","DOIUrl":"10.1016/j.micres.2025.128429","url":null,"abstract":"<div><div>Pyocyanin is the primary phenazine produced by <em>Pseudomonas aeruginosa</em>, which possesses redox activity. This compound contributes to its virulence by generating reactive oxygen species and inducing oxidative stress in prokaryotic and eukaryotic cells. <em>P. aeruginosa</em> is able to resist high concentrations of pyocyanin despite its toxicity. In this work, we employed <em>P. aeruginosa</em> ID4365 and PAO1 <em>rsmA</em> mutants, which produce 276.2 μM and 6.9 μM of pyocyanin, respectively, to conduct a proteomic analysis in order to identify proteins involved in the protective response against this phenazine. We found that inactivation of <em>rsmA</em> in ID4365 altered the levels of 474 proteins, including those related to the oxidative stress response, efflux pumps, and chaperones. While in PAO1, <em>rsmA</em> inactivation affected the levels of 177 proteins, and only MexH, which is part of the MexGHI-OpmD efflux pump involved in exporting pyocyanin, was identified as a protein related to the protective response. We further determined whether RsmA controls the pyocyanin protective response in ID4365 and found that expression of genes encoding OxyR, SoxR, and Fur, which are essential for oxidative stress defense and iron homeostasis, were negatively regulated by RsmA. Moreover, we demonstrate that RsmA negatively controls the GroESL chaperone system, suggesting its role in alleviating pyocyanin-induced proteotoxic stress. Our findings indicate that the protective response against pyocyanin is more pronounced in ID4365 compared to the PAO1 strain when <em>rsm</em>A is deleted. Thus, RsmA plays a crucial role in this strain by regulating the response to prevent damage caused by pyocyanin overproduction.</div></div>","PeriodicalId":18564,"journal":{"name":"Microbiological research","volume":"305 ","pages":"Article 128429"},"PeriodicalIF":6.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145820131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2026-01-04DOI: 10.1016/j.micres.2026.128437
Jiacan Xu , Junnan Fang , Ruigang Wu , Yichen Wang , Chun Zhang , Xuming Wang , Tianlei Qiu
Maize yields rely heavily on chemical fertilizers, yet over half of the applied nitrogen remains unutilized, and excessive use harms soil, highlighting the need for sustainable alternatives. Plant growth-promoting rhizobacteria (PGPR) enhance plant growth and stress resistance, providing sustainable agricultural solutions. Here, we isolated Enterobacter vonholyi Y16 from the maize rhizosphere, and demonstrated multiple plant growth-promoting traits, including phosphate solubilization, potassium solubilization, siderophore secretion, and indole-3-acetic acid biosynthesis. An integrated approach combining rhizosphere microbiome profiling with plant transcriptomics was employed to elucidate the mechanisms of gene expression changes underlying PGPR-induced maize growth promotion. Inoculation with Y16 significantly increased primary root length in Arabidopsis thaliana by 16.7 %, and enhanced maize plant height, stem diameter, fresh shoot weight, and fresh root weight by 18.41 %, 22.32 %, 48.41 %, and 62.31 %, respectively. Strain Y16 successfully colonized the rhizosphere and influenced bacterial community composition under sterile soil conditions. Transcriptomic analysis revealed Y16-mediated regulation of key pathways, including plant hormone signaling, mitogen-activated protein kinase signaling, phenylpropanoid biosynthesis, and starch and sucrose metabolism. Notably, auxin-responsive genes were upregulated, correlating with Y16 abundance. These findings provide theoretical evidence for the molecular mechanisms of plant growth promotion by PGPR and offer insights for advancing sustainable agricultural development.
{"title":"Exploring the genomic features and plant growth-promoting properties of Enterobacter vonholyi Y16 isolated from maize rhizosphere","authors":"Jiacan Xu , Junnan Fang , Ruigang Wu , Yichen Wang , Chun Zhang , Xuming Wang , Tianlei Qiu","doi":"10.1016/j.micres.2026.128437","DOIUrl":"10.1016/j.micres.2026.128437","url":null,"abstract":"<div><div>Maize yields rely heavily on chemical fertilizers, yet over half of the applied nitrogen remains unutilized, and excessive use harms soil, highlighting the need for sustainable alternatives. Plant growth-promoting rhizobacteria (PGPR) enhance plant growth and stress resistance, providing sustainable agricultural solutions. Here, we isolated <em>Enterobacter vonholyi</em> Y16 from the maize rhizosphere, and demonstrated multiple plant growth-promoting traits, including phosphate solubilization, potassium solubilization, siderophore secretion, and indole-3-acetic acid biosynthesis. An integrated approach combining rhizosphere microbiome profiling with plant transcriptomics was employed to elucidate the mechanisms of gene expression changes underlying PGPR-induced maize growth promotion. Inoculation with Y16 significantly increased primary root length in <em>Arabidopsis thaliana</em> by 16.7 %, and enhanced maize plant height, stem diameter, fresh shoot weight, and fresh root weight by 18.41 %, 22.32 %, 48.41 %, and 62.31 %, respectively. Strain Y16 successfully colonized the rhizosphere and influenced bacterial community composition under sterile soil conditions. Transcriptomic analysis revealed Y16-mediated regulation of key pathways, including plant hormone signaling, mitogen-activated protein kinase signaling, phenylpropanoid biosynthesis, and starch and sucrose metabolism. Notably, auxin-responsive genes were upregulated, correlating with Y16 abundance. These findings provide theoretical evidence for the molecular mechanisms of plant growth promotion by PGPR and offer insights for advancing sustainable agricultural development.</div></div>","PeriodicalId":18564,"journal":{"name":"Microbiological research","volume":"305 ","pages":"Article 128437"},"PeriodicalIF":6.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145926819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2025-12-19DOI: 10.1016/j.micres.2025.128420
Xuyang Zhang , Zhanyou Liu , Guilan Ma , Fan Dai , Wu Li
Staphylococcus aureus (S. aureus) is a major human pathogen that causes apoptosis of immune cells during infection. The rate of apoptosis influences the severity and outcome of the disease, and can be fatal in conditions such as sepsis and septicemia. Dual-specificity phosphatase-1 (DUSP1) is a negative regulator of the mitogen-activated protein kinase (MAPK) signaling pathway in the host innate immune response. However, its role in S. aureus-induced apoptosis remains unexplored. In this study, we investigated the function and underlying regulatory mechanisms of DUSP1 in S. aureus-induced apoptosis. This study revealed that S. aureus infection induces DUSP1 expression and promotes apoptosis. DUSP1 knockdown promotes S. aureus-induced apoptosis, accumulation of reactive oxygen species, and expression of MAPK family member proteins, leading to increased lung tissue injury and poorer intracellular bacterial survival. Furthermore, S. aureus infection elevates the expression of immunoglobulin heavy chain-binding protein (BIP), promotes apoptosis, and enhances the binding of DUSP1 to BIP. Inhibition of BIP enhances S. aureus-induced apoptosis and MAPK signaling pathways. Taken together, these findings demonstrate that S. aureus infection induces DUSP1 and BIP expression, leading to cell apoptosis, and that DUSP1 interacts with BIP to regulate S. aureus-induced apoptosis through the MAPK signaling pathway. Our findings support the regulatory role of DUSP1 in S. aureus-mediated apoptosis, suggesting that DUSP1 is a potential anti-apoptotic therapeutic target.
{"title":"DUSP1 interacts with BIP to regulate Staphylococcus aureus-induced apoptosis through the MAPK signaling pathway","authors":"Xuyang Zhang , Zhanyou Liu , Guilan Ma , Fan Dai , Wu Li","doi":"10.1016/j.micres.2025.128420","DOIUrl":"10.1016/j.micres.2025.128420","url":null,"abstract":"<div><div><em>Staphylococcus aureus</em> (<em>S. aureus</em>) is a major human pathogen that causes apoptosis of immune cells during infection. The rate of apoptosis influences the severity and outcome of the disease, and can be fatal in conditions such as sepsis and septicemia. Dual-specificity phosphatase-1 (DUSP1) is a negative regulator of the mitogen-activated protein kinase (MAPK) signaling pathway in the host innate immune response. However, its role in <em>S. aureus</em>-induced apoptosis remains unexplored. In this study, we investigated the function and underlying regulatory mechanisms of DUSP1 in <em>S. aureus</em>-induced apoptosis. This study revealed that <em>S. aureus</em> infection induces DUSP1 expression and promotes apoptosis. DUSP1 knockdown promotes <em>S. aureus</em>-induced apoptosis, accumulation of reactive oxygen species, and expression of MAPK family member proteins, leading to increased lung tissue injury and poorer intracellular bacterial survival. Furthermore, <em>S. aureus</em> infection elevates the expression of immunoglobulin heavy chain-binding protein (BIP), promotes apoptosis, and enhances the binding of DUSP1 to BIP. Inhibition of BIP enhances <em>S. aureus</em>-induced apoptosis and MAPK signaling pathways. Taken together, these findings demonstrate that <em>S. aureus</em> infection induces DUSP1 and BIP expression, leading to cell apoptosis, and that DUSP1 interacts with BIP to regulate <em>S. aureus</em>-induced apoptosis through the MAPK signaling pathway. Our findings support the regulatory role of DUSP1 in <em>S. aureus</em>-mediated apoptosis, suggesting that DUSP1 is a potential anti-apoptotic therapeutic target.</div></div>","PeriodicalId":18564,"journal":{"name":"Microbiological research","volume":"305 ","pages":"Article 128420"},"PeriodicalIF":6.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2025-10-30DOI: 10.1016/j.micres.2025.128383
Yongheng Hou , Shiguang Huang , Xin-zhuan Su , Fangli Lu
Autophagy is a catabolic process that responds to various environmental stresses, such as nutrient deficiency and intracellular pathogen infection. Toxoplasma gondii is an intracellular parasite that acquires nutrients from the host cells for its proliferation; however, the molecular mechanisms of T. gondii parasites’ nutritional acquisition and metabolism are not fully understood. Here, we found that T. gondii type I RH strain induced host cell autophagy for nutrient acquisition and growth. T. gondii RH strain infection induced DNA damage-regulated autophagy modulator 1 (DRAM1) expression in host cells, and mechanistic analyses suggest an involvement of the IL-33-MyD88-p38/NF-κB signaling pathway in this process. DRAM1 knockdown decreased T. gondii parasite growth, while DRAM1 overexpression increased T. gondii parasite growth by hyperactivating autophagy, especially lipophagy, to provide fatty acids for T. gondii proliferation, which led to increased tissue pathology. This study identified DRAM1 as a critical molecule in regulating type I T. gondii-induced lipophagy, parasite proliferation, and liver pathology in mice. The results provide crucial insights into how T. gondii leverages host autophagy for its gain and identify a target for potential disease management, which may offer new avenues for developing novel drugs against this parasite.
{"title":"DNA damage-regulated autophagy modulator 1 (DRAM1)-induced lipophagy facilitates Toxoplasma gondii nutrient acquisition and infection","authors":"Yongheng Hou , Shiguang Huang , Xin-zhuan Su , Fangli Lu","doi":"10.1016/j.micres.2025.128383","DOIUrl":"10.1016/j.micres.2025.128383","url":null,"abstract":"<div><div>Autophagy is a catabolic process that responds to various environmental stresses, such as nutrient deficiency and intracellular pathogen infection. <em>Toxoplasma gondii</em> is an intracellular parasite that acquires nutrients from the host cells for its proliferation; however, the molecular mechanisms of <em>T. gondii</em> parasites’ nutritional acquisition and metabolism are not fully understood. Here, we found that <em>T. gondii</em> type I RH strain induced host cell autophagy for nutrient acquisition and growth. <em>T. gondii</em> RH strain infection induced DNA damage-regulated autophagy modulator 1 (DRAM1) expression in host cells, and mechanistic analyses suggest an involvement of the IL-33-MyD88-p38/NF-κB signaling pathway in this process. DRAM1 knockdown decreased <em>T. gondii</em> parasite growth, while DRAM1 overexpression increased <em>T. gondii</em> parasite growth by hyperactivating autophagy, especially lipophagy, to provide fatty acids for <em>T. gondii</em> proliferation, which led to increased tissue pathology. This study identified DRAM1 as a critical molecule in regulating type I <em>T. gondii</em>-induced lipophagy, parasite proliferation, and liver pathology in mice. The results provide crucial insights into how <em>T. gondii</em> leverages host autophagy for its gain and identify a target for potential disease management, which may offer new avenues for developing novel drugs against this parasite.</div></div>","PeriodicalId":18564,"journal":{"name":"Microbiological research","volume":"305 ","pages":"Article 128383"},"PeriodicalIF":6.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145820122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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