DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for gonorrhea — 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 moduleGonorrhea 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
approvedDoxycyclineApproved drug
Structures already discussed alongside gonorrhea in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
Crystal structure of Alpha1-antichymotrypsin variant DBS-I1: a drug-binding serpin for doxycycline — Doxycycline has a real, experimentally solved structure in complex with this target (PDB 5OM2, 1.47 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 dxtdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5OM2 · 1.47 Å · ligand Doxycycline (DXT). Experimental structure, not a prediction.
What the evidence adds up to
Gonorrhoea cases are rising globally and an increasing proportion are multidrug-resistant. Resistance has been reported even to extended-spectrum cephalosporins, the mainstay of current therapy. As of 2017 only three new chemical entities were in clinical development for gonorrhoea. In 2014 a modelling study found that eliminating oral therapy in favour of exclusive ceftriaxone (given by intramuscular injection) could lead to fewer infected persons being cured overall, partly because the change would likely eliminate the use of patient-delivered partner therapy. In that model, if at least 5% of oral therapy recipients went untreated after the switch, universal ceftriaxone use resulted in fewer cures among index cases. When partner treatment effects were included, exclusive ceftriaxone consistently led to fewer infected persons being cured.
Single-dose oral therapy with ciprofloxacin (500 mg) or cefixime (400 mg) eliminated Neisseria gonorrhoeae from urine within 4 hours and from mucosa within 24 hours in 14 men with symptomatic urethritis, and from semen within 24 hours in 9 additional subjects. These results support the efficacy of single-dose oral therapy and suggest rapid elimination reduces the risk of continued transmission. However, the 2014 modelling study noted that if oral treatment were 75% effective against decreased-susceptibility gonorrhoea, exclusive ceftriaxone use would likely increase cure rates in persons with decreased-susceptibility strains but could diminish them in persons with gonorrhoea overall.
Host genetic factors may influence susceptibility. In a longitudinal study of 485 adolescents, a haplotype of the interleukin-2 gene (promoter −330T and intron 1 −166G) was more frequent in those who had gonorrhoea (relative odds 3.2). Among 388 females, endocervical IL-2 concentrations were lower during active infection, and the decrease was mostly restricted to carriers of that haplotype. Two human leukocyte antigen variants were also independently associated with gonorrhoea: Cw*04 increased risk (adjusted relative odds 1.9) and DQB1*05 decreased risk (adjusted relative odds 0.5). The authors noted these immunogenetic correlates need confirmation in larger cohorts.
N. gonorrhoeae adapts to the fluctuating environment of the female genital tract by modulating gene expression through DNA-binding transcriptional regulators. Understanding these regulatory mechanisms and their interaction with the genital tract microbiome has been proposed as a route to new treatment or prevention strategies, but no such strategies have yet been tested in humans. What remains missing is investment in the clinical development of the few new chemical entities in the pipeline, larger studies to confirm immunogenetic targets for vaccine design, and trial designs that account for the real-world effects of switching from oral to injectable-only therapy on patient adherence and partner treatment.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
PLoS Medicine · 2017 · 162 citations · open access
Multidrug-resistant gonorrhea: A research and development roadmap to discover new medicines
AbstractThe number of gonorrhea cases is rising in many settings worldwide, and an increasing proportion of cases are multidrug-resistant. The choice of antimicrobials that can be used for treatment of gonorrhea is very limited, and resistance has even been reported to extended-spectrum cephalosporins, which are the mainstay of currently recommended antimicrobial therapy. Currently, only 3 new chemical entities are in different stages of clinical development for treatment of gonorrhea.
New England Journal of Medicine · 1967 · 71 citations
Diagnosis and Treatment of Gonorrhea in the Female
AbstractSEVERAL factors inherent in the natural history of gonorrhea have prevented successful control. The short incubation period, the lack of natural or acquired resistance, decreasing sensitivity to penicillin and changing moral standards are frequently cited as leading reasons why this disease continues to flourish.Another important basic obstacle is the asymptomatic nature of gonorrhea in the female. It is seldom realized that a high percentage of females are completely symptomless and unaware that they are infected. This carrier state provides a reservoir that serves to perpetuate the infection within the population. One of the greatest needs has been for a . . .
Time Required for Elimination of Neisseria gonorrhoeae from the Urogenital Tract in Men with Symptomatic Urethritis
AbstractBACKGROUND AND OBJECTIVES: The spread of sexually transmitted diseases (STDs), including gonorrhea, is affected by the duration of infection. Oral antibiotic therapy for gonococcal infection has been shown to be as effective as conventional intramuscular injection with ceftriaxone. Rapid cure would be expected to limit further spread of gonorrhea. However, the speed with which Neisseria gonorrhoeae is eliminated from the urogenital tract has not been evaluated. GOAL OF THIS STUDY: To determine the time required for elimination of Neisseria gonorrhoeae for the urine, mucosa, and semen in male subjects after treatment with ceftriaxone (250 mg intramuscularly), ciprofloxacin (500 mg by mouth, single dose) or cefixime (400 mg by mouth, single dose.) RESULTS: In 14 subjects, gonococci were eliminated from the urine within 4 hours of therapy and the mucosa within 24 hours after therapy. In 9 additional subjects, gonococci were eliminated from the semen by 24 hours after therapy. CONCLUSIONS: These results support the efficacy of single-dose oral therapy for gonorrhea and suggest that earlier follow-up for proof of cure in clinical trials of new antibiotics for gonorrhea may be acceptable. Rapid elimination of gonorrhea reduces the risk for continued transmission of the organism.
Immunogenetic Correlates of Neisseria gonorrhoeae Infection in Adolescents
AbstractIn Brief Background: Understanding host factors modulating immunity to Neisseria gonorrhoeae infection may benefit work on vaccine development. Methods: We analyzed longitudinal data collected from 485 male and female adolescents to determine genetic correlates of genital gonorrhea. Cytokine data from 388 females were analyzed to assess immunologic markers of gonorrhea and their relationship to genetic correlates. Results: The T-G haplotype defining interleukin-2 (IL-2) gene promoter and intron 1 polymorphisms (−330T and −166G) was more frequently found in individuals who had gonorrhea (relative odds = 3.2, P = 0.01). Among 3 endocervical cytokines measured, IL-10 and IL-12 concentrations were higher and IL-2 lower when gonorrhea was detected. The decrease in endocervical IL-2 after gonorrhea acquisition was mostly restricted to subjects with the IL2 T-G haplotype, which may reflect involvement of a pathogen-specific and genetically mediated mechanism for differential IL-2 responses at genital mucosa. In addition, 2 human leukocyte antigen variants (Cw*04 and DQB1*05) were also independently associated with gonorrhea (adjusted relative odds = 1.9 and 0.5, respectively; P <0.05 for both). Conclusions: Confirmation of immunogenetic correlates of gonorrhea in larger cohorts may be useful in guiding further research on both innate and adaptive immune responses to N. gonorrhoeae. Analyses of longitudinal data from 485 adolescents revealed that subjects with a haplotype corresponding to interleukin-2 gene variants −330T and 166G more often had gonorrhea; cytokine analyses in 388 female adolescents demonstrated this haplotype was correlated with reduced endocervical interleukin-2 concentration during active infection.
Potential Deleterious Effects of Promoting the Use of Ceftriaxone in the Treatment of Neisseria gonorrhoeae
AbstractBACKGROUND: US gonorrhea treatment guidelines recently changed to promote ceftriaxone as first-line therapy. Because ceftriaxone requires intramuscular administration, this could lead some patients to go untreated. METHODS: We used an arithmetic model to compare the number of persons with gonorrhea who would be successfully treated with continued use of oral therapies versus exclusive use of ceftriaxone. Our base case scenario assumed the following: decreased cefixime susceptibility in 2% of heterosexuals and 5% of men who have sex with men, baseline oral therapy in 30% of heterosexuals and 15% of men who have sex with men, oral treatment failure in 10% of decreased susceptibility cases, and baseline patient-delivered partner therapy use in 30% of heterosexuals. RESULTS: Considering only effects on index cases, universal ceftriaxone use would result in fewer cures if at least 5% of oral therapy recipients go untreated with the change in treatment practice. Exclusive ceftriaxone use consistently led to fewer infected persons being cured when the model incorporated partner treatment effects and assumed that the change in treatment practices eliminated the use of patient delivered partner therapy. If oral treatment were 75% effective against decreased susceptibility gonorrhea, exclusive ceftriaxone use would likely increase cure rates in persons with decreased susceptibility gonorrhea, but could diminish them in persons with gonorrhea overall. CONCLUSIONS: At least in the short term, eliminating oral therapy for gonorrhea will likely have small effects on decreased susceptibility treatment failures and could increase gonorrhea rates overall.
Molecular Regulatory Mechanisms Drive Emergent Pathogenetic Properties of Neisseria gonorrhoeae
AbstractNeisseria gonorrhoeae is the causative agent of the sexually transmitted infection (STI) gonorrhea, with an estimated 87 million annual cases worldwide. N. gonorrhoeae predominantly colonizes the male and female genital tract (FGT). In the FGT, N. gonorrhoeae confronts fluctuating levels of nutrients and oxidative and non-oxidative antimicrobial defenses of the immune system, as well as the resident microbiome. One mechanism utilized by N. gonorrhoeae to adapt to this dynamic FGT niche is to modulate gene expression primarily through DNA-binding transcriptional regulators. Here, we describe the major N. gonorrhoeae transcriptional regulators, genes under their control, and how these regulatory processes lead to pathogenic properties of N. gonorrhoeae during natural infection. We also discuss the current knowledge of the structure, function, and diversity of the FGT microbiome and its influence on gonococcal survival and transcriptional responses orchestrated by its DNA-binding regulators. We conclude with recent multi-omics data and modeling tools and their application to FGT microbiome dynamics. Understanding the strategies utilized by N. gonorrhoeae to regulate gene expression and their impact on the emergent characteristics of this pathogen during infection has the potential to identify new effective strategies to both treat and prevent gonorrhea.
A Three-Day Doxycycline Regimen for Treatment of Gonorrhea
AbstractPatients with uncomplicated gonorrhea were given three 300-mg capsules of doxycycline, one of which was to be taken after the heaviest meal of the day, on each of three consecutive days. A total of 560 men and women were treated by this method. Of the 355 patients who returned for tests of cure within seven to ten days, all but seven (2%) responded favorably to the treatment. The effectiveness of the regimen was similar to that of other accepted treatments. Adverse effects were inconsequential or absent, providing that the medication was taken after meals. This treatment option simplifies considerably the directions to be followed by the patient and minimizes the risk of noncompliance in the treatment of gonorrhea with tetracyclines.
AbstractOne hundred ninety-two cases of gonorrhea, of which 23 were extragenital only or both genital and extragenital, were treated with a single oral dose of thiamphenicol (2.5 g in patients weighing less than or equal to 80 kg; 3 g in patients weighing greater than 80 kg). Of the 178 patients whose follow-up was possible, 176 patients (98.9%), including all 23 with extragenital infection (seven pharyngeal and 16 anorectal), recovered completely. The efficacy of the regimen compared favorably with that of other regimens currently used for the treatment of gonorrhea.
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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