Tidgewell, K. J. | Search bioRxiv

bioRxiv2026

Antibiotics modulate activity of mouse and human dorsal root ganglia neurons

Antibiotics are among the most prescribed medications worldwide, yet their direct effects on eukaryotic tissues remain largely unexplored. Here, we used in vitro calcium imaging to determine if clinically relevant concentrations of common antibiotics alter mouse and human dorsal root ganglion (DRG) neuron activity. We found that {beta}-lactams, macrolides, and tetracyclines induce calcium flux in sensory neurons within minutes of application. Regardless of antibiotic class, neuronal responses depend on extracellular calcium entry. Pharmacological manipulations further revealed that cephalexin responses depend on TRPA1 activity whereas doxycycline responses require mitochondrial reactive oxygen species (ROS) production. These findings demonstrate that clinically relevant concentrations of antibiotics directly modulate sensory neuron activity through divergent mechanisms, thus expanding our current understanding of antibiotic side effects.

neuroscience↗

bioRxiv2025

Neurobiological and Chemical Characterization of the Cyanobacterial Metabolite Veraguamide E

Ver Es structure was validated by {superscript 1}H NMR, HRMS, and molecular networking analyses. Computational docking and NMR titration confirmed direct, saturable, and tight binding of Ver E to the human Sigma-2 receptor/transmembrane protein 97 ({sigma}2R/TMEM97). Functional calcium imaging in primary mouse sensory neurons revealed that Ver E increases intracellular Ca{superscript 2} levels without modulating store-operated calcium entry (SOCE). Multi-well microelectrode array experiments using human induced pluripotent stem cell (hiPSC) derived nociceptors showed that Ver E significantly reduced neuronal activity at physiological temperatures, but not under heat-stress conditions. Ver E exhibited no cytotoxicity at concentrations up to 30 {micro}M in HEK293 cells, and immunocytochemistry confirmed that it does not alter phosphorylated eIF2 (p-eIF2) expression, indicating a mechanism distinct from integrated stress response modulators. Collectively, these findings position Ver E as a non-toxic compound capable of selectively modulating neuronal excitability, thereby advancing the development of novel therapeutics for pain management. SignificanceNatural products have long been recognized as a rich source of therapeutics, accounting for over 60% of currently approved small-molecule drugs and underscoring their pivotal role in drug discovery. Marine cyanobacteria produce structurally diverse secondary metabolites with a wide array of biological activities. Among these are the veraguamides, a family of depsipeptides that have shown promise as future therapeutics in our recent studies. This work presents a detailed biological and chemical characterization of veraguamide E (Ver E), isolated from a Panamanian marine cyanobacterial collection. The {sigma}2R/TMEM97 system has been identified as a promising target to address unmet need for non-opioid therapeutics which can modulate neuronal excitability in the context of chronic pain. Discovery and identification of novel compounds which modulate this system can help us better understand its function as well as allow us to develop future therapeutics targeting this pathway. HighlightsO_LIVeraguamide E specifically binds {sigma}2R/TMEM97 receptor with high affinity. C_LIO_LIComputational docking and NMR confirm a distinct binding mechanism. C_LIO_LIVer E modulates calcium signaling in mouse DRG neurons and human iPSC-derived nociceptors. C_LIO_LIVer E demonstrates no detectable cytotoxicity in human cell lines. C_LI

neuroscience↗

bioRxiv2025

Isolation and Bioassay of Linear Veraguamides from a Marine Cyanobacterium (Okeania sp.)

Marine cyanobacteria have gained momentum in recent years as a source of novel bioactive small molecules. This paper describes the structure elucidation and pharmacological evaluation of two new, veraguamide O (1) and veraguamide P (2), and one known, veraguamide C(3), analogs isolated from a cyanobacterial collection made in the Las Perlas Archipelago of Panama. We hypothesized that these compounds would be cytotoxic in cancer cell lines. The compounds were screened against HEK-293, estrogen receptor positive (MCF-7), and triple-negative breast cancer (MDA-MB-231) cells as well as against a broad panel of membrane bound receptors. The planar structures were determined based on NMR and MS data along with comparison to previously isolated veraguamide analogs. Phylogenetic analysis of the collection suggests it to be an Okeania sp., a similar species to the cyanobacterium reported to produce other veraguamides. Veraguamide O shows no cytotoxicity (greater than 100 M) against ER positive cells (MCF-7) with 13 M IC50 against MDA-MB-231 TNBC cells. Interestingly, these compounds show affinity for the sigma2/TMEM-97 receptor making them potential leads for development of non-toxic sigma 2 targeting ligands.

cancer biology↗