DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for legionellosis — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleLegionellosis maps to a 2-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 legionellosis 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
DNA topoisomerase II alpha (TOP2A) — TOP2A 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 5s,5ar,8ar,9rdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6ZY5 · 3.6 Å · ligand (5S,5aR,8aR,9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-8-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol
-5-yl 4,6-O-[(1R)-ethylidene]-beta-D-glucopyranoside (EVP). Experimental structure, not a prediction.
What the evidence adds up to
In a 2001 community outbreak in Murcia, Spain, 292 patients with Legionella pneumonia were studied prospectively but not randomised. All but two patients were cured. For mild-to-moderate pneumonia there was no significant difference between levofloxacin and macrolides. For severe pneumonia, levofloxacin was associated with fewer complications (3.4% versus 27.2%, P=0.02) and shorter mean hospital stay (5.5 versus 11.3 days, P=0.04). Adding rifampicin to levofloxacin provided no additional benefit. A 2014 systematic review and meta-analysis covering 12 studies and 879 patients found no randomised controlled trial directly comparing quinolones and macrolides for legionellosis. Among 253 patients on quinolone monotherapy, 10 died (4.0%); among 211 on macrolide monotherapy, 23 died (10.9%). The pooled odds ratio for death with quinolones versus macrolides was 0.5 (95% CI 0.2–1.3). Length of stay was significantly shorter with quinolones by 3.0 days (95% CI 0.7–5.3, P=0.001). Other outcomes, including clinical cure and time to apyrexia, were not significantly different.
A 2007 review states that macrolides and new quinolones remain the mainstay therapy, with early administration key for severe cases and immunocompromised patients. Among macrolides, azithromycin and clarithromycin have a better pharmacokinetic profile than erythromycin. Among quinolones, the more recent agents offer the best intrinsic activity against Legionella, but the clinical implications of these differences are unknown because most patients seem to be cured if treated early. Preliminary data on ketolides, gatifloxacin, garenoxacin, olaflumoxacin, tigecycline, and ziracin are described as encouraging, but more clinical experience is needed. Combined therapy is suggested for the most severe cases, particularly those requiring mechanical ventilation.
A 2010 update notes that legionellosis is an emerging and often fatal pneumonia most severe in elderly and immunocompromised people. The 2009 Legionella conference reported advances in understanding the genetic and metabolic basis of the intracellular lifestyle of Legionella and its ability to manipulate host cells by molecular mimicry, which may lead to new treatment and prevention approaches. A 2014 review of host-pathogen interaction describes that Legionella translocates approximately 300 effector proteins into host cells via the Dot/Icm type IV secretion system, which is central to pathogenesis.
What is still missing is a randomised controlled trial directly comparing quinolones and macrolides, which the 2014 meta-analysis explicitly calls for. The observational data show a trend but cannot establish superiority. The clinical relevance of in vitro differences among newer drugs remains unknown. No non-antibiotic therapy has been validated. Patient stratification by severity is used in existing studies, but no trial has prospectively stratified by immune status or comorbidity. Funding for a definitive trial and for development of non-antibiotic approaches is lacking.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Antimicrobial Chemotherapy for Legionnaires Disease: Levofloxacin versus Macrolides
AbstractBACKGROUND: The community outbreak of legionnaires disease that occurred in Murcia, Spain, in July 2001--to our knowledge, the largest such outbreak ever reported--afforded an unusual opportunity to compare the clinical response of patients with Legionella pneumonia treated with levofloxacin with that of patients treated with macrolides and to determine the role of rifampicin combined with levofloxacin in treating severe legionellosis. METHODS: An observational, prospective, nonrandomized study was conducted involving 292 patients seen at our hospital (Hospital "J. M. Morales Meseguer"; Murcia, Spain) who received a diagnosis of Legionella pneumonia during the Murcia outbreak. To compare both antibiotic regimens (macrolides vs. levofloxacin), patients were stratified by the severity of pneumonia. Duration of fever, clinical outcome, complications, side effects, and length of hospital stay were recorded. To assess the potential effects of adjuvant therapy with rifampicin, 45 case patients treated with levofloxacin plus rifampicin were evaluated and compared with 45 control pairs who were treated with levofloxacin alone. RESULTS: With the exception of 2 patients who died, all patients were cured. There were no significant differences between treatment groups in clinical outcome for patients with mild-to-moderate pneumonia. Nevertheless, in patients with severe pneumonia, levofloxacin exerted superior activity; it was associated with fewer complications (3.4% of patients receiving levofloxacin experienced complications, compared with 27.2% of patients receiving macrolides; P=.02) and shorter mean hospital stays (5.5 vs. 11.3 days; P=.04). Addition of rifampicin to the treatment regimen for patients receiveing levofloxacin for severe pneumonia provides no additional benefit. CONCLUSIONS: Our findings strongly suggest that monotherapy with levofloxacin is a safe and effective treatment for legionnaires disease, including in patients with severe disease. In these patients, levofloxacin appears to be more effective than clarithromycin.
Molecular Microbiology · 2010 · 62 citations · open access
Update on Legionnaires’ disease: pathogenesis, epidemiology, detection and control
AbstractLegionellosis or Legionnaires' disease is an emerging and often-fatal form of pneumonia that is most severe in elderly and immunocompromised people, an ever-increasing risk group for infection. In recent years, the genomics of Legionella spp. has significantly increased our knowledge of the pathogenesis of this disease by providing new insights into the evolution and genetic and physiological basis of Legionella-host interactions. The seventh international conference on Legionella, Legionella 2009, illustrated many recent conceptual advances in epidemiology, pathogenesis and ecology. Experts in different fields presented new findings on basic mechanisms of pathogen-host interactions and bacterial evolution, as well as the clinical management and environmental prevalence and persistence of Legionella. The presentations revealed remarkable facts about the genetic and metabolic basis of the intracellular lifestyle of Legionella and reported on its striking ability to manipulate host cell processes by molecular mimicry. Together, these investigations will lead to new approaches for the treatment and prevention of Legionnaires' disease.
Journal of Antimicrobial Chemotherapy · 2014 · 49 citations · open access
Quinolones versus macrolides in the treatment of legionellosis: a systematic review and meta-analysis
AbstractBACKGROUND: Legionellosis is a life-threatening disease. The clinical superiority of quinolones or macrolides for treating patients with legionellosis has not been established. METHODS: We performed a systematic review and meta-analysis of studies reporting data that allowed the comparison of quinolones versus macrolides in the treatment of proven legionellosis published from 1 January 1985 to 31 January 2013. We collected baseline aggregate patient characteristics. Studied outcomes included mortality, clinical cure, time to apyrexia, length of hospital stay and occurrence of complications in each treatment group. Treatment effect was assessed using a Mantel-Haenszel random effects model. RESULTS: Among 1005 abstracts reviewed, 12 studies were selected (n=879 patients). No randomized controlled trial was performed directly comparing quinolone and macrolide efficacy in legionellosis. Mean age was 58.3 years, 27.7% were women and Fine score was ≥ 4 in 35.8%. Among 253 patients who received quinolone monotherapy, 10 died (4.0%). Among 211 patients who received macrolide monotherapy, 23 died (10.9%). The pooled OR of death for treatment with a quinolone versus a macrolide was 0.5 (95% CI 0.2-1.3, n=8 studies, 464 patients). Length of stay was significantly shorter in the quinolone monotherapy group. The difference was 3.0 days (95% CI 0.7-5.3, P=0.001, n=3 studies, 263 patients). Neither of two tests for heterogeneity was significant (I (2)=0% for both, P=1). Other studied outcomes were not significantly different among treatment groups. CONCLUSIONS: Few clinical data on legionellosis treatment are available. This first meta-analysis showed a trend toward a lower mortality rate and a significant decrease in length of hospital stay among patients receiving quinolones. These results must be confirmed by a randomized controlled trial.
AbstractIn Brief Macrolides and new quinolones remain the mainstay therapy of Legionnaires disease. An early administration of effective therapy is a key factor for a successful outcome, especially in severe cases and in the immunocompromised population. Among macrolides, azithromycin and clarithromycin offer a better pharmacokinetic profile than erythromycin. New quinolones and azithromycin are both able to cause an irreversible inhibition of Legionella growth. Among quinolones, the more recent ones offer the best intrinsic activity against Legionella. However, the clinical implications of these differences of activity are unknown because most patients seem to be cured if properly treated early. Preliminary data on the activity of more recent drugs, such as ketolides, gatifloxacin, garenoxacin, olaflumoxacin, tigecycline or ziracin, are encouraging. However, more clinical experience is clearly warranted to establish their role in the treatment of legionellosis. Recent data suggest that combined therapy is useful in the most severe cases of legionellosis, particularly those that require mechanical ventilation. New drugs to treat Legionnaires disease have been recently licensed or are already in the last phase of their clinical development. Their potential role in the therapy of legionellosis is a challenging issue. The actual clinical usefulness of other innovative, non-antibiotic forms of therapy needs also to be elucidated.
The host-pathogen interaction of Legionella pneumophila
AbstractLegionella are gram-negative bacteria ubiquitously found in freshwater and soil environments. Once inhaled by humans, Legionella infection could result in a severe form of pneumonia known as Legionellosis. Legionella translocate ~300 effector proteins into host cells via the Dot/Icm type IV secretion system, which is central to Legionella pathogenesis. Here I describe a brief review on recent advances in research on the molecular basis of Legionella-eukaryotic-cell interaction.
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.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
