Biology subjects

Petersson, A.

Publications and source records attributed to Petersson, A..

2 recordsLinked to original sources

bioRxiv2023

Apramycin efficacy in the treatment of carbapenem-resistant Enterobacterales in murine blood stream infection models

BackgroundThe aminoglycoside apramycin has been proposed as a drug candidate for the treatment of critical Gram-negative systemic infections. However, its potential in the treatment of drug-resistant bloodstream infections (BSIs) has yet to be assessed. MethodsThe resistance gene annotations of 26 493 blood culture isolates were analyzed. In vitro profiling of apramycin comprised cell-free translation assays, broth microdilution, and frequency of resistance determination. The efficacy of apramycin was studied in a mouse peritonitis model for nine E. coli and K. pneumoniae isolates. ResultsGenotypic aminoglycoside resistance was identified in 87.8% of all 6973 carbapenem-resistant Enterobacterales blood-culture isolates, in comparison to 46.4% of colistin and 2.1% of apramycin resistance. Apramycin activity against methylated ribosomes was > 100-fold higher than other aminoglycosides. Frequencies of resistance were < 10-9 at 8 x MIC. Tentative epidemiological cutoffs (ECOFFs) were determined as 8 g/mL for E. coli and 4 g/mL for K. pneumoniae. A single dose of 5 to 13 mg/kg resulted in a 1-log CFU reduction in the blood and peritoneum. Two doses of 80 mg/kg, resulting in an exposure that resembles the AUC observed for a single 30 mg/kg dose in humans, resulted in complete eradication of carbapenem- and aminoglycoside-resistant bacteremias. ConclusionEncouraging coverage and potent in-vivo efficacy against a selection of highly drug-resistant Enterobacterales isolates in the mouse peritonitis model warrants further consideration of apramycin as a drug candidate for the treatment and prophylaxis of BSI.

microbiology↗

bioRxiv2021

Galectin-9 signaling drives breast cancer invasion through matrix

Aberration in expression and function of glycans and their binding proteins (lectins) in transformed cells constitutes one of the earliest discovered hallmarks of cancer. Galectins are a conserved family of lectins that can bind to {beta}-galactosides. Among them, the role of Galectin-9, a galectin with two carbohydrate binding domains in immune-tumor cell interactions has been well-established, although its effect on cancer cell behavior remains as yet unclear. In this study, we used a spectrum of cell lines from homeostatic breast cells to transformed non-invasive and invasive cell lines cultured in microenvironment-diverse conditions to show that Galectin-9 expression shows an elevation in association with invasiveness of breast cancer epithelia. Our observations were supported by immunohistochemical studies of breast tumors and adjacent normal-tissues from patients. Genetic perturbation of Galectin-9 as well as the pharmacological inhibition of activity using cognate inhibitors confirmed a positive correlation between Galectin-9 levels and the adhesion of the aggressive triple negative breast cancer cells MDA-MB-231 to- and their invasion through-extracellular matrices (ECM). Within a constituted organomimetic multiECM microenvironment, Galectin-9 enhanced both the solitary and the collective invasion of cancer cells. Quantitative proteomics led us to uncover the inductive role of Galectin-9 in the expression of the proinvasive protein S100A4. In addition, Galectin-9 expression correlated with FAK signaling, the inhibition of which decreased S100A4 mRNA levels. Our results provide crucial signaling insights into how the elevation in Galectin-9 expression in breast cancer cells potentiates their invasiveness through ECM during early steps of metastasis.

cancer biology↗