Clinical Pharmacist and Master’s student in Clinical Pharmacy with research interests in pharmacovigilance, behavioral interventions in mental health, and AI applications in clinical decision support. Experience includes digital health research with Bloomsbury Health (London) and pharmacovigilance practice in patient support programs. Published work covers drug awareness among healthcare providers, postpartum depression management, and patient safety reporting. What was studied?
This original research article investigated the genetic determinants enabling Group B Streptococcus (GBS; Streptococcus agalactiae) to survive in the bloodstream, with a particular focus on the role of the glyoxalase pathway in methylglyoxal (MG) detoxification and its impact on virulence. Using a comprehensive in vivo transposon (Tn) mutant screen in a murine bacteremia model, the authors identified 623 genes significantly underrepresented in blood, many of which encode known virulence factors such as capsule, β-hemolysin/cytolysin, and metal ion transporters. Notably, the study discovered that GBS homologs of glyoxalase A (gloA) and B (gloB) were essential for survival, implicating the glyoxalase pathway in resistance to host-derived MG. The functional significance of gloA was further validated via mutagenesis, complementation, and infection assays, demonstrating its necessity for MG tolerance, survival against neutrophils, and invasive disease.
Who was studied?
The subjects of this study were both bacterial and mammalian. The bacterial component comprised various clinical isolates of GBS, notably the CJB111 (serotype V), A909 (serotype Ia), and COH1 (serotype III) strains, representing different MG tolerance phenotypes. These strains were genetically manipulated to create gloA deletion mutants and complemented strains. The mammalian subjects were primarily 6–8-week-old male CD-1 mice used for the in vivo bacteremia infection model, with additional experiments involving neutrophil depletion. Human-derived HL60 neutrophil-like cells and primary murine bone marrow neutrophils were utilized for in vitro killing assays, elucidating the interaction between GBS and host immune defenses, particularly the role of neutrophil-produced MG.
Most important findings
| Critical Points | Details |
|---|---|
| Glyoxalase pathway, especially gloA, is crucial for GBS survival in blood | Disruption of gloA or gloB led to marked reductions in bacterial survival in murine blood. Both genes were significantly underrepresented in the Tn-seq dataset (fold changes –18.38 and –25.63, respectively), highlighting their essential roles for in vivo fitness. |
| GloA mediates MG detoxification and resistance | ∆gloA mutants accumulated higher intracellular MG and showed increased sensitivity to exogenous MG, as evidenced by prolonged growth lag and reduced cell density in the presence of MG. Complementation restored MG tolerance, confirming gloA’s role in detoxification. |
| Strain-dependent variation in MG tolerance | Among tested GBS isolates, MG resistance varied independently of serotype or GloA amino acid sequence. Serotype III strains (COH1) exhibited higher baseline expression of glyoxalase genes and greater MG resistance, potentially linked to gene regulation rather than sequence variation. |
| GloA deletion impairs virulence and survival against neutrophils | In vivo, ∆gloA mutants demonstrated reduced mortality, lower bacterial burdens in blood and organs, and diminished ability to cause invasive infection. In vitro, ∆gloA strains were more susceptible to killing by HL60-derived and primary murine neutrophils. Neutrophil depletion in mice restored virulence of the ∆gloA mutant, suggesting MG produced by neutrophils is a key host defense. |
| Metal ion transporters are also critical for GBS survival | Genes encoding for zinc, manganese, nickel, and copper transporters were significantly underrepresented, indicating that trace metal acquisition is essential for GBS blood survival. Notably, the nickel transporter may support GloA activity, as GloA is nickel-dependent in some bacteria. |
| Host-pathogen metabolic interplay impacts GBS pathogenesis | Neutrophil-produced MG increased upon GBS infection, as detected by anti-MG antibody flow cytometry. This underscores the importance of metabolic host defenses and bacterial countermeasures for successful pathogenesis. |
Key implications
This research provides evidence that the glyoxalase pathway, particularly gloA, is vital for GBS resistance to host-derived MG and invasive disease, highlighting MG detoxification as a key survival mechanism. The findings also reinforce the significance of metal ion transport systems for bacterial fitness. For heavy metal certification programs, these results stress the need to monitor and regulate microbial metal resistance and detoxification pathways, as they directly influence pathogen virulence and host interactions.
Citation
Akbari MS, Joyce LR, Spencer BL, Brady A, McIver KS, Doran KS. Identification of glyoxalase A in group B Streptococcus and its contribution to methylglyoxal tolerance and virulence. Infection and Immunity. 2025;93(4):e00540-24. doi:10.1128/iai.00540-24
