Biology subjects

Mello, S. S.

Publications and source records attributed to Mello, S. S..

3 recordsLinked to original sources

bioRxiv2025

Efagins evolved independently to target the enterococcal cell wall

Enterococci are major causes of multidrug-resistant infections, and antimicrobials with fundamentally new mechanisms of action are urgently needed. We identify a new class of antibacterial agents, termed efagins, which are chromosomally encoded, phage-related nanomachines that recognize cell wall carbohydrate receptors and inhibit subsets of E. faecalis, E. faecium and other enterococci selectively--a key reason they evaded prior detection. Five natural variants with distinct targeting profiles were identified - four related by sequence divergence, while one appears to have arisen through recombination of the targeting domain, likely from a phage donor. Operons encoding the corresponding carbohydrate receptors are highly variable, accounting for targeting specificity. The efagin targeting domain can be engineered to reprogram them toward alternative receptors, providing a pathway for filling critical coverage gaps. These findings advance efagins as new selective antibacterials with promise for addressing infection and spread of multidrug-resistant enterococcal infection.

microbiology↗

bioRxiv2024

Drug-Induced p53 Activation Promotes Acinar Cell Identity and Prevents Pancreatic Cancer Initiation

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease, initiated predominantly by mutations in Kras, which induce acinar-to-ductal metaplasia (ADM) and subsequent formation of precursor lesions, such as pancreatic intraepithelial neoplasia (PanIN). Progression to PDAC is frequently associated with mutations in the tumor suppressor TP53, presumably via disrupting p53-mediated cellular senescence of PanINs. Whether TP53 also has tumor-suppressive activity in earlier phases of PDAC initiation has been less clear. In this study, we investigate the impact of pharmacological stabilization of the wild-type p53 protein on the formation of ADM in a KrasG12D-driven mouse model of PDAC. Our findings demonstrate that p53 stabilization via Nutlin-3a significantly reduces both ADM and PanIN formation by promoting the differentiation of ADM into acinar cells. This differentiation coincides with p53-dependent upregulation of the transcription factor Mist1 (Bhlha15), a critical inducer of acinar cell identity. Our results reveal a role for p53 in tissue repair and maintenance of homeostasis in tumor suppression and suggest pharmacological engagement of p53 as an intervention strategy to prevent PDAC initiation.

cancer biology↗

bioRxiv2023

MYC disrupts transcriptional and metabolic circadian oscillations in cancer and promotes enhanced biosynthesis

The molecular circadian clock, which controls rhythmic 24-hour oscillation of genes, proteins, and metabolites in healthy tissues, is disrupted across many human cancers. Deregulated expression of the MYC oncoprotein has been shown to alter expression of molecular clock genes, leading to a disruption of molecular clock oscillation across cancer types. It remains unclear what benefit cancer cells gain from suppressing clock oscillation, and how this loss of molecular clock oscillation impacts global gene expression and metabolism in cancer. We hypothesized that MYC or its paralog N-MYC (collectively termed MYC herein) suppress oscillation of gene expression and metabolism to upregulate pathways involved in biosynthesis in a static, non-oscillatory fashion. To test this, cells from distinct cancer types with inducible MYC were examined, using time-series RNA-sequencing and metabolomics, to determine the extent to which MYC activation disrupts global oscillation of genes, gene expression pathways, and metabolites. We focused our analyses on genes, pathways, and metabolites that changed in common across multiple cancer cell line models. We report here that MYC disrupted over 85% of oscillating genes, while instead promoting enhanced ribosomal and mitochondrial biogenesis and suppressed cell attachment pathways. Notably, when MYC is activated, biosynthetic programs that were formerly circadian flipped to being upregulated in an oscillation-free manner. Further, activation of MYC ablates the oscillation of nutrient transporter proteins while greatly upregulating transporter expression, cell surface localization, and intracellular amino acid pools. Finally, we report that MYC disrupts metabolite oscillations and the temporal segregation of amino acid metabolism from nucleotide metabolism. Our results demonstrate that MYC disruption of the molecular circadian clock releases metabolic and biosynthetic processes from circadian control, which may provide a distinct advantage to cancer cells.

cancer biology↗