Selection for Resistance to a Glyphosate-Containing Herbicide in Salmonella enterica Does Not Result in a Sustained Activation of the Tolerance Response or Increased Cross-Tolerance and Cross-Resistance to Clinically Important Antibiotics.

Evolution of bacterial tolerance to antimicrobials precedes evolution of resistance and may result in cross-tolerance, cross-resistance, or collateral sensitivity to other antibiotics. Transient exposure of gut bacteria to glyphosate, the world's most widely used herbicide, has been linked to the activation of the stress response and changes in susceptibility to antibiotics. In this study, we investigated whether chronic exposure to a glyphosate-based herbicide (GBH) results in resistance, a constitutive activation of the tolerance and stress responses, and cross-tolerance or cross-resistance to antibiotics. Of the 10 farm animal-derived clinical isolates of Salmonella enterica subjected to experimental evolution in increasing concentrations of GBH, three isolates showed stable resistance with mutations associated with the glyphosate target gene aroA and no fitness costs. Global quantitative proteomics analysis demonstrated activation of the cellular tolerance and stress response during the transient exposure to GBH but not constitutively in the resistant mutants. Resistant mutants displayed no cross-resistance or cross-tolerance to antibiotics. These results suggest that while transient exposure to GBH triggers cellular tolerance response in Salmonella enterica, this response does not become genetically fixed after selection for resistance to GBH and does not result in increased cross-tolerance or cross-resistance to clinically important antibiotics under our experimental conditions.IMPORTANCE Glyphosate-based herbicides (GBH) are among the world's most popular, with traces commonly found in food, feed, and the environment. Such high ubiquity means that the herbicide may come into contact with various microorganisms, on which it acts as an antimicrobial, and it may select for resistance and cross-resistance to clinically important antibiotics. It is therefore important to estimate whether the widespread use of pesticides may be an underappreciated source of antibiotic-resistant microorganisms that may compromise efficiency of antibiotic treatments in humans and animals.

Nicorandil attenuates neuronal mitochondrial dysfunction and oxidative stress associated with murine model of vascular calcification.

Evidences suggest that the presence of chronic kidney disease (CKD) is associated with cerebrovascular diseases related cognitive decline in dialysis patients. As mitochondrial dysfunction is implicated in neurodegenerative disorders, we hypothesized that changes in brain mitochondria occur due to vascular calcification induced by renal failure and the opening of the mitochondrial potassium channel using nicorandil may prevent its dysfunction. Brain tissues from rats with vascular calcification were studied. Nicorandil (7.5 mg/kg b.wt.) was given either concomitantly or after the induction of calcification. The brain tissues were evaluated for antioxidant capacity, mitochondrial enzymes and oxidative phosphorylation efficiency along with the progression of calcification. The results suggested that renal failure, elevated the calcium, phosphorus product in the brain. The brain cytoplasm and mitochondrial fractions showed an elevated TBARS and a corresponding decline in the antioxidant enzymes, indicating a sev ere oxidative stress. The elevated brain mitochondrial enzymes like NADH dehydrogenase, and succinate dehydrogenase in the disease control groups, reversed to the near control level after nicorandil treatment. We observed that nicorandil was more effective when given after calcification. It reduced the biochemical alterations associated with calcium and phosphorous toxicity in the brain, by preserving mitochondria, the key target for treating neurodegenerative diseases.