Naidu, V. | bioRxiv Science

bioRxiv2025

Multi Omics Driven Polypharmacology for Osteoarthritis Joint Regeneration

Osteoarthritis (OA) is a common degenerative condition of major joints with no effective cure. Yograj Guggulu (YG) is a well-established polyherbal formulation in Indian traditional medicine for the management of joint disorders. However, its mode of action remains unclear. We integrated multi omics network analysis with a rat model to investigate the effects of oral administration of YG on osteoarthritic joints. YG administration significantly alleviated pain and improved joint function. Imaging and histological analyses reveal that YG protects against structural degeneration in the joint with OA. Proteomic and metabolomic profiling, along with network analysis, uncovered that multiple components of YG alter protein expression in key pathways related to inflammation and cartilage degradation, thus validating the observed clinical effects. The efficacy of YG seems to be the result of the synergistic action of its diverse constituents. Our findings support the use of YG as a multitarget therapy for OA and encourage efforts for the potential repurposing of its active components.

systems biology↗

bioRxiv2020

Spermidine and spermine are the natural substrates of the Acinetobacter baumannii AmvA multidrug efflux pump

Multidrug efflux pumps are important drivers of antibiotic resistance in Acinetobacter baumannii and other pathogens, however their natural roles beyond transport of clinical antimicrobials are poorly described. Polyamines are an ancient class of molecules with broad roles in all three kingdoms of life, and are the likely natural substrate of at least one efflux pump family. We have defined the transcriptome of A. baumannii following treatment with high levels of the polyamines putrescine, cadaverine, spermidine and spermine. These molecules influenced expression of multiple gene classes in A. baumannii including those associated with virulence, and the four polyamines induced distinct but overlapping transcriptional responses. Polyamine shock also induced expression of the MFS-family efflux pump gene amvA and its repressor gene amvR. Loss of amvA dramatically reduced tolerance to the long-chain triaamine spermidine, but caused only modest changes in resistance to known AmvA substrates such as acriflavine. We confirmed reduced accumulation of spermidine in amvA-deficient A. baumannii, and showed that its expression is induced by long-chain polyamines through its cognate regulator AmvR. Our findings suggest that the conserved A. baumannii efflux pump AmvA has evolved to export spermidine from the cell, but that its substrate recognition promiscuity also allows activity against clinically-important biocides and antibiotics. ImportanceAMR genes, including multidrug efflux pumps, evolved long before the ubiquitous use of antimicrobials in medicine and infection control. Multidrug efflux pumps often transport metabolites, signals and host-derived molecules in addition to antibiotics or biocides. Understanding the ancestral physiological roles of multidrug efflux pumps could help to inform the development of strategies to subvert their activity. In this study, we investigated the response of Acinetobacter baumannii to polyamines, a widespread, abundant class of amino acid-derived metabolites, which led us to identify long-chain polyamines as natural substrates of the disinfectant efflux pump AmvA. A second clinically-important efflux pump, AdeABC, also contributed to polyamine tolerance. Our results suggest that the disinfectant resistance capability that allows A. baumannii to survive in hospitals may have evolutionary origins in the transport of polyamine metabolites.

microbiology↗