Unraveling the Antimicrobial and Antibiofilm Activity of Ag-phendione and Cu-phendione Against Multidrug-resistant Klebsiella pneumoniae Using Shotgun Proteomics Gabriela Seabra, Victor Corasolla Carregari, Inglid Souza da Mata, Domingos da Silva Leite, Andre Souza dos Santos, et al. Current Topics in Medicinal Chemistry, 2026 Introduction: Multidrug-resistant (MDR) Klebsiella pneumoniae infections are associated with high mortality, prolonged hospitalization, and limited treatment options, representing a global healthcare challenge. The coordination compounds [Ag(1,10-phenanthroline-5,6- dione)2]ClO4 (Ag-phendione) and [Cu(1,10-phenanthroline-5,6-dione)3(ClO4)2] (Cu-phendione) have previously demonstrated antimicrobial and antibiofilm activity against MDR Gram-negative bacilli. Methods: This study investigated their mechanisms of action by combining classical microbiology with shotgun proteomics. Minimum inhibitory and bactericidal concentrations (MIC/MBC), timekill assay, and antibiofilm effects were determined, while nanoESI-LC-MS/MS identified proteins modulated in MDR K. pneumoniae. Results: MIC values ranged from 3.125 mg/L to 12.5 mg/L for Ag-phendione and from 12.5 mg/L to 50 mg/L for Cu-phendione. Both compounds exhibited early antimicrobial effects ( ≤ 3 h), inhibited biofilm formation, and disrupted mature biofilms in a dose-dependent manner. Proteomic analysis revealed modulation of proteins related to NAD⁺ synthesis, carbohydrate metabolism (notably trehalose), DNA replication and repair, oxidoreductase activity, and plasmid partitioning. Discussion: The modulation of these proteins correlates with the observed antimicrobial and antibiofilm activity of the coordination compounds, suggesting potential targets for further validation. Interestingly, several proteins modulated by these compounds are also affected by classical antibiotics such as meropenem and colistin, suggesting partially convergent mechanisms involving central metabolism and redox homeostasis. Conclusion: Ag-phendione and Cu-phendione are promising candidates for the development of novel therapeutics against MDR K. pneumoniae. Future studies should validate key targets through genetic knockouts or enzyme activity assays to clarify the mechanisms underlying these effects.
Transcriptome of iPSC-derived neuronal cells reveals a module of co-expressed genes consistently associated with autism spectrum disorder K. Griesi-Oliveira, M. S. Fogo, B. G. G. Pinto, A. Y. Alves, A. M. Suzuki, et al. Molecular Psychiatry, 2021 Evaluation of expression profile in autism spectrum disorder (ASD) patients is an important approach to understand possible similar functional consequences that may underlie disease pathophysiology regardless of its genetic heterogeneity. Induced pluripotent stem cell (iPSC)-derived neuronal models have been useful to explore this question, but larger cohorts and different ASD endophenotypes still need to be investigated. Moreover, whether changes seen in this in vitro model reflect previous findings in ASD postmortem brains and how consistent they are across the studies remain underexplored questions. We examined the transcriptome of iPSC-derived neuronal cells from a normocephalic ASD cohort composed mostly of high-functioning individuals and from non-ASD individuals. ASD patients presented expression dysregulation of a module of co-expressed genes involved in protein synthesis in neuronal progenitor cells (NPC), and a module of genes related to synapse/neurotransmission and a module related to translation in neurons. Proteomic analysis in NPC revealed potential molecular links between the modules dysregulated in NPC and in neurons. Remarkably, the comparison of our results to a series of transcriptome studies revealed that the module related to synapse has been consistently found as upregulated in iPSC-derived neurons—which has an expression profile more closely related to fetal brain—while downregulated in postmortem brain tissue, indicating a reliable association of this network to the disease and suggesting that its dysregulation might occur in different directions across development in ASD individuals. Therefore, the expression pattern of this network might be used as biomarker for ASD and should be experimentally explored as a therapeutic target.
Ubiquitin–proteasome system, lipid metabolism and DNA damage repair are triggered by antipsychotic medication in human oligodendrocytes: implications in schizophrenia Gabriela Seabra, Valéria de Almeida, Guilherme Reis-de-Oliveira, Fernanda Crunfli, André Saraiva Leão Marcelo Antunes, et al. Scientific Reports, 2020 Schizophrenia is a chronic, severe and disabling psychiatric disorder, whose treatment is based on psychosocial interventions and the use of antipsychotic drugs. While the effects of these drugs are well elucidated in neuronal cells, they are still not so clear in oligodendrocytes, which play a vital role in schizophrenia. Thus, we aimed to characterize biochemical profiles by proteomic analyses of human oligodendrocytes (MO3.13) which were matured using a protocol we developed and treated with either haloperidol (a typical antipsychotic), clozapine (an atypical antipsychotic) or a clozapine + d-serine co-treatment, which has emerged lately as an alternative type of treatment. This was accomplished by employing shotgun proteomics, using nanoESI-LC–MS/MS label-free quantitation. Proteomic analysis revealed biochemical pathways commonly affected by all tested antipsychotics were mainly associated to ubiquitination, proteasome degradation, lipid metabolism and DNA damage repair. Clozapine and haloperidol treatments also affected proteins involved with the actin cytoskeleton and with EIF2 signaling. In turn, metabolic processes, especially the metabolism of nitrogenous compounds, were a predominant target of modulation of clozapine + d-serine treatment. In this context, we seek to contribute to the understanding of the biochemical and molecular mechanisms involved in the action of antipsychotics on oligodendrocytes, along with their possible implications in schizophrenia.
Proteomics and Lipidomics in the Elucidation of Endocannabinoid Signaling in Healthy and Schizophrenia Brains Gabriela Seabra, Ana Caroline B. Falvella, Paul C. Guest, Daniel Martins‐de‐Souza, Valéria de Almeida Proteomics, 2018 Interest in the modulation of endocannabinoid signaling has increased since the discovery of receptors for compounds of Cannabis sativa . Endocannabinoids are crucial neuromodulators of many brain functions and changes in the ligands and their receptors have been associated with psychiatric disorders, such as schizophrenia. Genetic, neuroimaging, and behavioral studies have reinforced the role of endocannabinoids in the pathobiology of schizophrenia. However, molecular pathways and biological processes involved in cannabinoid effects are not totally understood. Additionally, the endocannabinoid signaling network with other non‐cannabinoid targets, and the effects of phytocannabinoids increase the complexity to understand their role in schizophrenia and homeostasis conditions. Thus, proteomic studies can provide evidence about the involvement of cannabinoid receptors, as well as the metabolic and synthetic enzymes of the endocannabinoids in these disorders. Additionally, quantification of endocannabinoids in the blood serum or cerebrospinal fluid can be a useful approach to identify new biomarkers in schizophrenia, and lipidomic techniques can be used to quantify these compounds. Herein, the authors review proteomic and lipidomic studies that have been used for analysis of the endocannabinoid system in healthy and schizophrenia function. The findings may contribute to understand the involvement of endocannabinoids in the brain and in the neurobiological basis of schizophrenia.
RECENT SCHOLAR PUBLICATIONS
Bakterion: development of a serious game for microbiology education LR Campos, HV de Morais, G Seabra, KV dos Santos, DCSA de Araújo Brazilian Journal of Medical and Biological Research 58, e14866 , 2025 2025
Cannabinoids modulate proliferation, diferentiation, and migration signaling pathways in oligodendrocytes V de Almeida, G Seabra, G Reis-de-Oliveira, GS Zuccoli, P Rumin, ... Eur Arch Psychiatry Clin Neurosci, doi.org/10.1007/s00406-022-01425-5 , 2022 2022 Citations: 10
Transcriptome of iPSC-derived neuronal cells reveals a module of co-expressed genes consistently associated with autism spectrum disorder K Griesi-Oliveira, MS Fogo, BGG Pinto, AY Alves, AM Suzuki, AG Morales, ... Molecular psychiatry 26 (5), 1589-1605 , 2021 2021 Citations: 95
Azithromycin use in COVID-19 patients: Implications on the antimicrobial resistance G Seabra, RFV Mendes, LFV Amorim, IV Peregrino, MH Branquinha, ... Curr. Top. Med. Chem 21 (8), 677-683 , 2021 2021 Citations: 7
Ubiquitin–proteasome system, lipid metabolism and DNA damage repair are triggered by antipsychotic medication in human oligodendrocytes: implications in schizophrenia G Seabra, V de Almeida, G Reis-de-Oliveira, F Crunfli, ASLM Antunes, ... Scientific reports 10 (1), 12655 , 2020 2020 Citations: 21
Novel treatment strategies targeting myelin and oligodendrocyte dysfunction in schizophrenia D Gouvêa-Junqueira, ACB Falvella, ASLM Antunes, G Seabra, ... Frontiers in Psychiatry 11, 379 , 2020 2020 Citations: 71
Novel treatment strategies targeting myelin and oligodendrocyte dysfunction in schizophrenia. Front Psychiatry 11: 379 D Gouvêa-Junqueira, ACB Falvella, A Antunes, G Seabra, ... doi. org/10.3389/fpsyt , 2020 2020 Citations: 3
Maturation of a human oligodendrocyte cell line G Seabra, V de Almeida, D Martins-de-Souza Pre-Clinical Models: Techniques and Protocols, 113-121 , 2018 2018 Citations: 3
Proteomics and lipidomics in the elucidation of endocannabinoid signaling in healthy and schizophrenia brains G Seabra, ACB Falvella, PC Guest, D Martins‐de‐Souza, V de Almeida Proteomics 18 (18), 1700270 , 2018 2018 Citations: 17
T194. Evaluating the Effects of Antipsychotics on Human Oligodendrocytes by Proteomic Analysis G Seabra, V de Almeida, DM de Souza Biological Psychiatry 83 (9), S203 , 2018 2018
F198. Effects of cannabinoids on a human oligodendrocyte culture: Implications for schizophrenia V Almeida, G Seabra, JA Crippa, JE Hallak, AW Zuardi, ... Schizophrenia Bulletin 44 (suppl_1), S297-S298 , 2018 2018 Citations: 1
MOST CITED SCHOLAR PUBLICATIONS
Transcriptome of iPSC-derived neuronal cells reveals a module of co-expressed genes consistently associated with autism spectrum disorder K Griesi-Oliveira, MS Fogo, BGG Pinto, AY Alves, AM Suzuki, AG Morales, ... Molecular psychiatry 26 (5), 1589-1605 , 2021 2021 Citations: 95
Novel treatment strategies targeting myelin and oligodendrocyte dysfunction in schizophrenia D Gouvêa-Junqueira, ACB Falvella, ASLM Antunes, G Seabra, ... Frontiers in Psychiatry 11, 379 , 2020 2020 Citations: 71
Ubiquitin–proteasome system, lipid metabolism and DNA damage repair are triggered by antipsychotic medication in human oligodendrocytes: implications in schizophrenia G Seabra, V de Almeida, G Reis-de-Oliveira, F Crunfli, ASLM Antunes, ... Scientific reports 10 (1), 12655 , 2020 2020 Citations: 21
Proteomics and lipidomics in the elucidation of endocannabinoid signaling in healthy and schizophrenia brains G Seabra, ACB Falvella, PC Guest, D Martins‐de‐Souza, V de Almeida Proteomics 18 (18), 1700270 , 2018 2018 Citations: 17
Cannabinoids modulate proliferation, diferentiation, and migration signaling pathways in oligodendrocytes V de Almeida, G Seabra, G Reis-de-Oliveira, GS Zuccoli, P Rumin, ... Eur Arch Psychiatry Clin Neurosci, doi.org/10.1007/s00406-022-01425-5 , 2022 2022 Citations: 10
Azithromycin use in COVID-19 patients: Implications on the antimicrobial resistance G Seabra, RFV Mendes, LFV Amorim, IV Peregrino, MH Branquinha, ... Curr. Top. Med. Chem 21 (8), 677-683 , 2021 2021 Citations: 7
Novel treatment strategies targeting myelin and oligodendrocyte dysfunction in schizophrenia. Front Psychiatry 11: 379 D Gouvêa-Junqueira, ACB Falvella, A Antunes, G Seabra, ... doi. org/10.3389/fpsyt , 2020 2020 Citations: 3
Maturation of a human oligodendrocyte cell line G Seabra, V de Almeida, D Martins-de-Souza Pre-Clinical Models: Techniques and Protocols, 113-121 , 2018 2018 Citations: 3
F198. Effects of cannabinoids on a human oligodendrocyte culture: Implications for schizophrenia V Almeida, G Seabra, JA Crippa, JE Hallak, AW Zuardi, ... Schizophrenia Bulletin 44 (suppl_1), S297-S298 , 2018 2018 Citations: 1
Bakterion: development of a serious game for microbiology education LR Campos, HV de Morais, G Seabra, KV dos Santos, DCSA de Araújo Brazilian Journal of Medical and Biological Research 58, e14866 , 2025 2025
T194. Evaluating the Effects of Antipsychotics on Human Oligodendrocytes by Proteomic Analysis G Seabra, V de Almeida, DM de Souza Biological Psychiatry 83 (9), S203 , 2018 2018
