DeCure's autonomous AMR AI scientist is researching a drug-repurposing hypothesis for Escherichia coli Infections — screening already-approved drugs against its 29-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleEscherichia coli Infections maps to a 29-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
approvedBosutinibApproved drug
Structures already discussed alongside escherichia coli infections in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
human Src kinase — Bosutinib has a real, experimentally solved structure in complex with this target (PDB 4MXO, 2.105 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet db8drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4MXO · 2.105 Å · ligand Bosutinib (DB8). Experimental structure, not a prediction.
What the evidence adds up to
In a three-year randomised trial of 105 diabetic women with asymptomatic Escherichia coli bacteriuria, those assigned to antibiotic treatment had bacteriuria for 29% of follow-up time, compared with 66% in untreated women. The average duration of a single bacteriuria episode was 2.2 months in the treated group versus 3.7 months in the untreated group. However, 76% of treated women had recurrent infection, and 64% of those recurrences were caused by a genetically new E. coli strain. The infecting strains lacked the virulence factors typical of uropathogenic E. coli and resembled faecal isolates from healthy women. Treatment reduced the proportion of time colonised but did not prevent recolonisation, usually with a different strain.
A retrospective cohort study of 220 patients with carbapenem-resistant Enterobacteriaceae (CRE) infections compared colistin monotherapy (67 patients) with colistin-fosfomycin combination therapy (153 patients). After propensity score weighting, 30-day mortality was not significantly different between the groups (adjusted odds ratio 1.51, 95% CI 0.60–3.78). Mortality at end of treatment, clinical response, and microbiologic response were also similar. The study found no advantage of adding fosfomycin to colistin for CRE infections.
In laboratory and animal work, the tyrosine kinase inhibitor bosutinib was tested against mcr-1-positive E. coli. In vitro, bosutinib combined with colistin restored colistin susceptibility, increased bacterial membrane permeability, raised reactive oxygen species, and directly bound the MCR-1 protein. In an infected animal model, the combination increased survival and reduced tissue bacterial load. These are preclinical findings only.
What is still missing: no prospective randomised trial has tested bosutinib plus colistin in humans; the colistin-fosfomycin comparison was retrospective and from a single hospital; the asymptomatic bacteriuria trial showed that treatment does not prevent reinfection and may select for new strains, but did not address clinical outcomes such as pyelonephritis or hospitalisation. Patient stratification by resistance mechanism, adequate funding for a bosutinib-colistin trial, and a trial design that accounts for recurrent infection are all absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Long‐Term<i>Escherichia coli</i>Asymptomatic Bacteriuria among Women with Diabetes Mellitus
AbstractBACKGROUND: Persistent Escherichia coli asymptomatic bacteriuria (ASB) is common among persons with diabetes mellitus, but the duration of colonization and the rates of recolonization are unknown. We estimated the duration of colonization and the rate of recolonization among successively isolated E. coli from diabetic women with ASB and compared the virulence profiles with uropathogenic and commensal E. coli. METHODS: A total of 105 women with diabetes were enrolled in a randomized, controlled clinical trial for treatment of ASB in Manitoba, Canada, and were observed at least every 3 months for up to 3 years. We analyzed 517 isolates from 70 women with repeated E. coli ASB for genetic similarity using enterobacterial repetitive intergenic consensus polymerase chain reaction. Unique strains were screened for uropathogenic virulence characteristics using dot blot hybridization and compared with different collections of E. coli isolates. RESULTS: On average, differences were found among women assigned to treatment for ASB, those treated only for symptomatic infections, and untreated women in (1) follow-up time with bacteriuria (29%, 31%, and 66%, respectively; P<.001), (2) duration of bacteriuria (2.2, 2.5, and 3.7 months, respectively; P=.04), and (3) carriage of unique isolates (2.4, 2.8, and 4 months, respectively; P=.03). Women assigned to antibiotic treatment usually had recurrent infection (76%), 64% of the time with a genetically new E. coli strain. Virulence characteristics of these isolates were comparable to those of fecal isolates from healthy women. CONCLUSIONS: Treatment may reduce the overall proportion of time infected in the long term and carriage of a unique strain, but most treatment regimens were followed by subsequent recolonization. Infecting strains did not have virulence factors characteristic of uropathogenic E. coli.
Journal of Infection and Public Health · 2024 · 30 citations · open access
Comparative effectiveness and mortality of colistin monotherapy versus colistin-fosfomycin combination therapy for the treatment of carbapenem-resistant Enterobacteriaceae (CRE) infections: A propensity score analysis
AbstractBACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) infections pose a significant threat to global health due to limited treatment options and high mortality rates. Colistin-based regimens have emerged as a primary treatment approach, but the effectiveness and mortality outcomes of colistin monotherapy versus colistin-fosfomycin combination therapy remain uncertain. This study aims to compare the effectiveness and mortality of colistin monotherapy and colistin-fosfomycin combination therapy for CRE infections. Notably, our study is the first to undertake a comprehensive examination of the effectiveness and mortality outcomes between colistin monotherapy and colistin-fosfomycin combination therapy in the context of CRE infections. METHODS: A retrospective cohort study was conducted using data from patients diagnosed with carbapenem-resistant Enterobacteriaceae (CRE) infections at Nakornping Hospital during 2015 to 2022. Inverse probability weighting (IPW) was employed to create balanced cohorts of patients receiving either colistin monotherapy or colistin-fosfomycin combination therapy. The primary outcome measure was treatment effectiveness, assessed by 30-day mortality. Secondary outcome measures included clinical response, mortality at the end of treatment, and microbiologic response. Univariate and multivariate logistic regression analysis were employed after applying propensity score weighting using inverse probability of weighting (IPW). RESULTS: A total of 220 patients were included in the analysis, with 67 receiving colistin monotherapy and 153 receiving colistin-fosfomycin combination therapy. Propensity score weighting using IPW balanced the baseline characteristics between the two groups. The effectiveness of treatment, as measured by 30-day mortality, was not significantly different between the colistin monotherapy group and the colistin-fosfomycin combination therapy group (adjusted odds ratio [aOR] = 1.51, 95% confidence interval [CI]: 0.60-3.78, p = 0.383). Similarly, no significant difference was observed in the mortality at the end of treatment between the two groups (aOR = 1.26, 95% CI: 0.55-2.90, p = 0.576). The clinical response (aOR = 1.48, 95% CI: 0.61-3.59, p = 0.383) and microbiologic response (aOR = 0.66, 95% CI: 0.18-2.38, p = 0.527) were similar between the colistin monotherapy and colistin-fosfomycin combination therapy groups. CONCLUSION: The propensity score analysis among 220 matched patients showed comparable treatment effectiveness and mortality between colistin monotherapy and colistin-fosfomycin combination therapy for CRE infections. These results suggest that colistin monotherapy may be as effective as combination therapy. More prospective randomized controlled trials are needed to confirm these findings and establish optimal CRE treatment strategies.
Bosutinib Restores the Sensitivity of Colistin against Mcr-1-Positive <i>E. coli</i>
AbstractPlasmid-mediated transmission of the mcr-1 gene significantly impairs the antimicrobial activity of colistin, limiting clinical therapeutic options. In this study, we evaluated the potential of bosutinib in restoring the susceptibility of colistin to mcr-1-positive drug-resistant Escherichia coli using a “drug repurposing” strategy and explored its mechanism of action to develop a new combination therapy regimen. We found that bosutinib combined with colistin significantly restored the susceptibility of mcr-1-positive E. coli to colistin and showed strong bactericidal and antibiofilm activities, confirmed by drug sensitivity assays, viable bacterial counts, and biofilm assays. Meanwhile, membrane permeability assay, reactive oxygen species (ROS) measurement, molecular docking, and SPR analysis showed that bosutinib could enhance bacterial membrane permeability, increase ROS accumulation, and directly bind to the MCR-1 protein, disrupting its resistance mechanism. Furthermore, in an infected animal model, bosutinib combined with colistin significantly increased the survival and reduced the bacterial load in tissues, confirming its in vivo antimicrobial efficacy. In conclusion, the present study reveals that bosutinib restores the antimicrobial activity of colistin through dual mechanisms: membrane permeability enhancement and direct targeting of the MCR-1 protein. Indeed, the discovery of bosutinib not only expands the application of tyrosine kinase inhibitor analogues in the field of anti-infective drugs but also provides a potentially new alternative for the clinical treatment of MCR-1-positive bacterial infections.
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.
