Tropheryma whipplei the causative agent of Whipple disease, presents a diagnostic challenge due to its diverse symptomatology, including weight loss, abdominal pain, diarrhea, joint pain, fever, and occasionally neurological manifestations. Its resistance to fluoroquinolones complicates treatment further. Traditional methods for antibiotic susceptibility testing are ineffective as Tropheryma whipplei cannot be cultured in axenic media. To address this, we explored potential drug targets within its core genome as no drug targets from this bacterium have been studied so far. murE, a macrolide-resistant enzyme, emerged as a promising candidate exhibiting both resistance and drug target characteristics. We screened over 1,000 lead-like Ayurvedic compounds against the target enzyme UDP-N-acetylmuramyl-tripeptide synthetase and identified three promising candidates: (1) Ergost-5-en-3-ol (3beta,24xi), (2) [6]-Gingerdiol 3-monoacetate, and (3) Valtrate. DiffDock and GNINA rescoring yielded consistent binding strength rankings. Molecular dynamics simulations over 100 nanoseconds confirmed stable interactions with these compounds. ADMET analysis indicated low water solubility, but coupling with cyclodextrin SBE-β-CD improved solubility. None of the compounds showed hepatotoxic effects, though Valtrate exhibited AMES toxicity. Based on the favorable properties, we propose scaffold hopping and further in vitro/in vivo studies on [6]-Gingerdiol 3-monoacetate. Our findings offer potential avenues for combating T. whipplei infections, addressing the limitations posed by antibiotic resistance.

Background: Cancer is a leading cause of death globally. Accurate cancer burden information is crucial for policy planning, but many countries do not have up-to-date cancer surveillance data. To inform global cancer-control efforts, we used the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 framework to generate and analyse estimates of cancer burden for 47 cancer types or groupings by age, sex, and 204 countries and territories from 1990 to 2023, cancer burden attributable to selected risk factors from 1990 to 2023, and forecasted cancer burden up to 2050. Methods: Cancer estimation in GBD 2023 used data from population-based cancer registration systems, vital registration systems, and verbal autopsies. Cancer mortality was estimated using ensemble models, with incidence informed by mortality estimates and mortality-to-incidence ratios (MIRs). Prevalence estimates were generated from modelled survival estimates, then multiplied by disability weights to estimate years lived with disability (YLDs). Years of life lost (YLLs) were estimated by multiplying age-specific cancer deaths by the GBD standard life expectancy at the age of death. Disability-adjusted life-years (DALYs) were calculated as the sum of YLLs and YLDs. We used the GBD 2023 comparative risk assessment framework to estimate cancer burden attributable to 44 behavioural, environmental and occupational, and metabolic risk factors. To forecast cancer burden from 2024 to 2050, we used the GBD 2023 forecasting framework, which included forecasts of relevant risk factor exposures and used Socio-demographic Index as a covariate for forecasting the proportion of each cancer not affected by these risk factors. Progress towards the UN Sustainable Development Goal (SDG) target 3.4 aim to reduce non-communicable disease mortality by a third between 2015 and 2030 was estimated for cancer. Findings: In 2023, excluding non-melanoma skin cancers, there were 18·5 million (95% uncertainty interval 16·4 to 20·7) incident cases of cancer and 10·4 million (9·65 to 10·9) deaths, contributing to 271 million (255 to 285) DALYs globally. Of these, 57·9% (56·1 to 59·8) of incident cases and 65·8% (64·3 to 67·6) of cancer deaths occurred in low-income to upper-middle-income countries based on World Bank income group classifications. Cancer was the second leading cause of deaths globally in 2023 after cardiovascular diseases. There were 4·33 million (3·85 to 4·78) risk-attributable cancer deaths globally in 2023, comprising 41·7% (37·8 to 45·4) of all cancer deaths. Risk-attributable cancer deaths increased by 72·3% (57·1 to 86·8) from 1990 to 2023, whereas overall global cancer deaths increased by 74·3% (62·2 to 86·2) over the same period. The reference forecasts (the most likely future) estimate that in 2050 there will be 30·5 million (22·9 to 38·9) cases and 18·6 million (15·6 to 21·5) deaths from cancer globally, 60·7% (41·9 to 80·6) and 74·5% (50·1 to 104·2) increases from 2024, respectively. These forecasted increases in deaths are greater in low-income and middle-income countries (90·6% [61·0 to 127·0]) compared with high-income countries (42·8% [28·3 to 58·6]). Most of these increases are likely due to demographic changes, as age-standardised death rates are forecast to change by –5·6% (–12·8 to 4·6) between 2024 and 2050 globally. Between 2015 and 2030, the probability of dying due to cancer between the ages of 30 years and 70 years was forecasted to have a relative decrease of 6·5% (3·2 to 10·3). Interpretation: Cancer is a major contributor to global disease burden, with increasing numbers of cases and deaths forecasted up to 2050 and a disproportionate growth in burden in countries with scarce resources. The decline in age-standardised mortality rates from cancer is encouraging but insufficient to meet the SDG target set for 2030. Effectively and sustainably addressing cancer burden globally will require comprehensive national and international efforts that consider health systems and context in the development and implementation of cancer-control strategies across the continuum of prevention, diagnosis, and treatment. Funding: Gates Foundation, St Jude Children's Research Hospital, and St Baldrick's Foundation.

Background: Rickettsia typhi is the causative agent of epidemic murine typhus and Rocky Mountain spotted fever. The infection can affect multiple vital organs, including the heart, lungs, kidneys, and brain. Doxycycline is the recommended treatment but inflammation, mal-response, and drug resistance may arise. No natural product inhibitors have been reported against this bacterium. Aim: The objective of this study was to establish a potential connection between autoimmune disorders triggered by R. typhi, identify therapeutic targets within its core proteome, and explore novel natural product inhibitors from Streptomyces spp. that could potentially inhibit it. Methodology: Complete proteomes of four publicly available R. typhi strains were used for pan-proteomic analysis. The fni gene product (Isopentenyl pyrophosphate isomerase) was selected as the potential drug target. Molecular docking of 607 Streptomyces-derived metabolites was performed, with top hits validated using DiffDock and Vinardo scoring. Additionally, the Absorption, Distribution, Metabolism, Excretion, and Toxicity properties of the leading compounds were assessed via pkCSM, and formulation characteristics optimized using FormulationAI. Results: Out of the 803 core proteins, associations between 14 proteins were mined for autoimmune diseases (including psoriasis, rheumatoid arthritis, optic atrophy, uveitis, even-plus syndrome, Sjogren syndrome, inflammatory bowel disease, allergic rhinitis, systemic lupus erythematosus, sclerosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, colitis etc.). 17 core proteins were predicted as druggable. ZINC01482946 demonstrated the strongest inhibitory potential, as confirmed by DiffDock scoring, convolutional neural network-based ranking, and Vinardo scoring. It demonstrated a stable configuration and exhibited a favorable pharmacokinetic profile, with bioavailability enhanced through cyclodextrin complexation. Conclusion: To the best of our knowledge, this is the first report identifying human autoimmune associations with R. typhi and natural product inhibitors targeting the pathogen. ZINC01482946 shows potential as an effective inhibitor of R. typhi, while SBE-β-CD appears to be a promising cyclodextrin for improving its solubility and bioavailability. Clinical trial number: Not applicable.