DeCure's autonomous AMR AI scientist is researching a drug-repurposing hypothesis for bacterial meningitis — screening already-approved drugs against its 4-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleBacterial meningitis maps to a 4-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for bacterial meningitis is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
prostaglandin-endoperoxide synthase 2 (PTGS2) — PTGS2 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet saldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5F1A · 2.38 Å · ligand 2-HYDROXYBENZOIC ACID (SAL). Experimental structure, not a prediction.
What the evidence adds up to
Penicillin and ampicillin remain the drugs of choice for meningitis caused by Streptococcus pneumoniae and Neisseria meningitidis, according to a review of studies published between 1975 and 1989. Third-generation cephalosporins, particularly ceftazidime, have changed treatment for gram-negative bacillary meningitis, including Pseudomonas aeruginosa. A study from that period found that adjunctive dexamethasone therapy in infants and children with bacterial meningitis lowered the incidence of long-term neurologic sequelae. Despite these advances, mortality and morbidity rates associated with bacterial meningitis remain unacceptably high, as noted in a 2007 review. A 2010 review states that when bacterial meningitis is suspected, antibiotic therapy should be initiated as soon as possible because early treatment is associated with a better outcome, and that dexamethasone has been shown to be helpful as adjuvant therapy in specific clinical situations.
Neisseria meningitidis is the leading cause of bacterial meningitis, a potentially fatal condition that particularly affects children, according to a 2004 review of host-pathogen interactions. The bacterium adheres to and enters a range of human cell types, which facilitates its ability to cause disease. Escherichia coli is the major Gram-negative bacterial pathogen in neonatal meningitis, a disease with high morbidity. Approximately 40% of survivors exhibit neurological sequelae, and neurologic complications often cannot be averted by antibiotic therapy alone, as stated in two 2014 and 2015 studies.
In mouse models of intracerebral E. coli infection, recombinant fragments of the outer membrane protein A (OmpA) have been tested. A 2014 study demonstrated that recombinant Loop 1-3, Loop 2-3, and Loop 2-4 fragments of OmpA can protect mice from death after intracerebral E. coli RS218 administration. A 2015 study confirmed that these same recombinant OmpA protein fragments (L1-3, L2-3, L2-4, and L3) can regulate cytokine, chemokine, nitric oxide synthase, and cyclooxygenase-2 expression and subsequently protect mice from death caused by intracerebral E. coli infection. The 2015 study also found that expression of interleukin-17 and other inflammatory mediators is involved in the inflammatory processes of intracerebral E. coli infection.
What is still missing is any evidence that these OmpA fragment approaches work in humans, not just in mice. No randomised controlled trials in patients with bacterial meningitis have been reported for any of these recombinant protein fragments. The clinical use of dexamethasone is limited to specific situations and does not prevent all neurological sequelae. The fundamental gaps remain: funding for human trials, proper patient stratification by pathogen and age group, and a trial design that can measure a reduction in the 40% neurological sequelae rate in survivors.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Annals of Internal Medicine · 1990 · 174 citations
Bacterial Meningitis: Recent Advances in Pathophysiology and Treatment
AbstractPURPOSE: To review recent advances in the understanding of pathogenic and pathophysiologic mechanisms underlying bacterial meningitis that may lead to the development of adjunctive strategies for treating this disorder. DATA IDENTIFICATION: Studies published from 1975 to 1989 were identified using Index Medicus and by reviewing the bibliographies of identified articles. STUDY SELECTION: We reviewed the experimental and human studies evaluating pathogenesis, pathophysiology, and antimicrobial treatment of bacterial meningitis, as well as those reviews that have contributed to our understanding of meningitis. DATA EXTRACTION: We evaluated the data on the pathogenesis, pathophysiology, and treatment of bacterial meningitis and considered in depth the information from animal models that may have potentially important applications in the treatment of human disease. RESULTS OF DATA SYNTHESIS: Penicillin and ampicillin remain the drugs of choice for meningitis caused by Streptococcus pneumoniae and Neisseria meningitidis. The third-generation cephalosporins have revolutionized the treatment of gram-negative bacillary meningitis; one such agent, ceftazidime, is also useful for treating Pseudomonas aeruginosa meningitis. Modification of subarachnoid space inflammation by anti-inflammatory agents may lessen many of the pathophysiologic consequences of bacterial meningitis. A recent study of adjunctive dexamethasone therapy in infants and children with bacterial meningitis showed that the incidence of long-term neurologic sequelae was lower in the corticosteroid group. CONCLUSION: Future therapy for bacterial meningitis will use recent developments in the understanding of pathogenic and pathophysiologic mechanisms underlying this disease. Additional studies using monoclonal antibodies against specific virulence factors and investigations into the production of inflammatory cytokines in response to bacterial cell products may lead to additional treatments that decrease the high morbidity and mortality in patients with bacterial meningitis.
Expert Opinion on Pharmacotherapy · 2007 · 34 citations
Bacterial meningitis: a review of effective pharmacotherapy
AbstractAcute bacterial meningitis is a serious and life-threatening neurological infectious disease. Despite the availability of effective antibiotics, supportive care facilities and recent advances in adjunctive strategies, for example, adjunctive dexamethasone, mortality and morbidity rates associated with bacterial meningitis remain unacceptably high. The review presents a brief overview of key clinical and epidemiological aspects of the disease and focuses on advances in pharmacotherapeutic strategies in adult patients with bacterial meningitis in the developed world.
The Evaluation and Management of Bacterial Meningitis
AbstractBACKGROUND AND OBJECTIVE: Bacterial meningitis is a serious neurologic illness with significant morbidity and mortality if not recognized and treated promptly and appropriately. The presentation and management are influenced by host factors and the pathogenic organism; the purpose of this review is to highlight those differences and to survey the literature on current practices and emerging developments in evaluation and management. REVIEW SUMMARY: Clinicians must have a high index of suspicion for bacterial meningitis. The classic symptoms of bacterial meningitis are fever, neck stiffness, altered mental status, and headache. Certain patient populations, such as the young and the immunocompromised, may have a blunted presentation, and for these patients, clinicians must have an especially low threshold for obtaining a lumbar puncture. When bacterial meningitis is suspected, antibiotic therapy should be initiated as soon as possible because early treatment is associated with a better outcome. In addition, the use of the corticosteroid dexamethasone has been shown to be helpful as an adjuvant therapy in specific clinical situations. New adjuvant therapies are being developed to lower the high rate of complications that currently occur in patients with bacterial meningitis. CONCLUSIONS: Recent studies have altered the evaluation and management of bacterial meningitis. In addition, they have elucidated the mechanisms through which bacterial meningitis causes complications and have identified new targets for treatment.
Expert Reviews in Molecular Medicine · 2004 · 9 citations
Interactions between <i>Neisseria meningitidis</i> and human cells that promote colonisation and disease
AbstractNeisseria meningitidis is the leading cause of bacterial meningitis, a potentially fatal condition that particularly affects children. Multiple steps are involved during the pathogenesis of infection, including the colonisation of healthy individuals and invasion of the bacterium into the cerebrospinal fluid. The bacterium is capable of adhering to, and entering into, a range of human cell types, which facilitates its ability to cause disease. This article summarises the molecular basis of host-pathogen interactions at the cellular level during meningococcal carriage and disease.
Journal of Microbiology Immunology and Infection · 2015 · 6 citations · open access
Recombinant OmpA protein fragments mediate interleukin-17 regulation to prevent Escherichia coli meningitis
AbstractBACKGROUND: Neonates are at a higher risk for bacterial meningitis than children of other age groups. Although the mortality rates have decreased over the past few decades, neonatal meningitis is still a severe disease with high morbidity. For bacterial meningitis, antibiotic therapy is the primary choice for management. However, neurologic complications often cannot be averted; ∼40% of survivors exhibit neurological sequelae. Escherichia coli infection is the common cause of neonatal meningitis. Previously, we have demonstrated that the recombinant loop 1-3, loop 2-3, and loop 2-4 fragments of OmpA protein can protect mice from death after intracerebral E. coli infection. In this study, the protective effects of the recombinant OmpA protein fragments in E. coli intracerebral infections were investigated. METHODS: The effects of E. coli intracerebral infection on cytokine and chemokine expression were determined. We also used various recombinant fragments of the OmpA protein to investigate the effects of these recombinant OmpA protein fragments on cytokine and chemokine expression. RESULTS: In this study, we demonstrated that the expression of interleukin-17 and other cytokines, chemokines, inducible nitric oxide synthase, and cyclooxygenase-2 are involved in the inflammatory processes of intracerebral E. coli infection. We also demonstrated that specific recombinant OmpA protein fragments (L1-3, L2-3, L2-4, and L3) can regulate cytokine, chemokine, nitric oxide synthase, and cyclooxygenase-2 expression and, subsequently, protect mice from death caused by intracerebral infection of E. coli. CONCLUSION: This finding indicates the potential for developing a new therapeutic approach to improve the prognosis of bacterial meningitis.
Journal of Microbiology Immunology and Infection · 2014 · 4 citations · open access
Recombinant outer membrane protein A fragments protect against Escherichia coli meningitis
AbstractBACKGROUND: Although the mortality rates have decreased over the past few decades, neonatal meningitis is still a severe disease with high morbidity. Moreover, approximately 40% of survivors exhibit neurological sequelae. Escherichia coli is the major Gram-negative bacterial pathogen in neonatal meningitis. The N-terminal β-barrel domain of the outer membrane protein A (OmpA) of E. coli is essential for effective protein conformation and function and contains four surface-exposed hydrophilic loops. In this study, we expressed different fragments of the four ring structures of the N-terminal domain, and investigated whether these recombinant OmpA fragments can protect mice from death after E. coli infection. METHODS: We expressed the recombinant proteins of the following OmpA fragments by using molecular cloning of Loop 1-2, Loop 1-3, Loop 1-4, Loop 2-3, Loop 2-4, and Loop 3-4. Animal experiments were subsequently performed to investigate the effects of these recombinant OmpA fragments on the survival of C57BL/6 mice after intracerebral E. coli RS218 administration. RESULTS: This study demonstrated that the recombinant Loop 1-3, Loop 2-3, and Loop 2-4 fragments of OmpA can protect mice from intracerebral E. coli infection. CONCLUSION: In bacterial meningitis, although antibiotic therapy is the first choice for management, neurological complications can seldom be averted. Based on the results of the present study, we intend to establish an effective therapeutic application for E. coli meningitis.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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