Amazing stuff! This could be a breakthrough! Towards better antibiotics! The article below is very well written!
This article also emphasizes the critical difference between studying bacteria isolated in a laboratory (in vitro) versus in the natural environment (in vivo).
"For years scientists have puzzled over why the intracellular pathogen Salmonella is able to survive — and thrive — in human and animal tissues, even within otherwise hostile cells that are part of the body’s immune system, such as white blood cells known as macrophages. ...
study reveals the molecular basis for the metabolic adaptations this pathogen undergoes that promotes its survival. ...
a team of ... researchers identify the process — including the role of a key signaling molecule that helps regulate carbon uptake in these organisms — that underlies the physiological changes governing Salmonella’s carbon source preference during infection.
Their findings also show that the behavioral changes commonly observed in Salmonella in laboratory settings don’t necessarily reflect how they behave in the natural environment ...
They also offer new insights into the role of metabolism in antibiotic tolerance, the researchers say.
“We know that Salmonella exhibits an increased tolerance to antibiotics when it is inside of macrophages,” ...
“These findings support a growing body of literature that implicates metabolism as a major foundation for antibiotic tolerance in bacteria,” ...
Bacteria, like all living organisms, rely on some form of carbon for most cellular processes — and their preferred or available diet plays a key role in their metabolism and physiology. Decades of research has shown that most microorganisms prefer glucose, a simple sugar, over other carbon sources.
The same is true for Salmonella enterica serovar Typhimurium, a common form of Salmonella — at least when it is grown in laboratory media. But when found inside macrophages, ... Salmonella’s so-called “carbon preference” becomes upended, showing instead a preference for alternative sources of carbon, such as gluconate and glycerol. This difference, researchers say, is likely the result of the host cell “starving” the pathogen of magnesium, an essential cofactor in hundreds of chemical reactions that fuel multiple cellular functions.
When a mammalian cell detects a pathogen, it responds by withholding magnesium. This forces the pathogen to carefully regulate the amount of magnesium it uses so that the cell doesn’t get the upper hand and eventually eliminate it. In Salmonella, the reduced concentration of magnesium induces changes in metabolism and other important physiological adjustments — including slower growth and increased tolerance to antibiotics.
Importantly, the researchers say, this infection-related stress changes pathogen metabolism by decreasing the amounts of cyclic adenosine monophosphate (cAMP), an essential activator of the master regulator of carbon utilization known as CRP (the cAMP receptor protein). This, in turn, decreases expression of carbon utilization genes, hindering carbon source uptake, and altering metabolism. ...
The findings may also offer new understanding of the dynamics of microbial metabolism beyond intracellular pathogenesis, such as in the gut microbiome, ... or even the role of metabolism in the growth of cancer cells.
“We may find that these findings have a much broader relevance outside of just Salmonella pathogenesis, given the fact that metabolism is so highly conserved across all domains of life and that magnesium is essential to all organisms,” ..."
From the significance and abstract:
"Significance
Carbon source preference is critical for bacterial metabolism and physiology. Most microorganisms utilize glucose over other carbon sources when grown in laboratory media with plentiful Mg2+.
However, pathogens such as Salmonella enterica serovar Typhimurium experience cytoplasmic Mg2+ starvation during infection of mammalian cells, resulting in alternative carbon sources being preferred over glucose. This altered preference results from cytoplasmic Mg2+ starvation decreasing the amount of the master regulator of carbon utilization, the cyclic adenosine monophosphate (cAMP) receptor protein (CRP) bound to its allosteric activator cAMP, and from the differential sensitivity of carbohydrate utilization genes to a decrease in CRP-cAMP amounts. Our findings explain why behaviors displayed by bacteria in their natural environments do not correspond to those reported for laboratory media.
Abstract
Glucose is the preferred carbon source of most studied microorganisms. However, we now report that glucose loses preferred status when the intracellular pathogen Salmonella enterica serovar Typhimurium experiences cytoplasmic magnesium (Mg2+) starvation.
We establish that this infection-relevant stress drastically reduces synthesis of cyclic adenosine monophosphate (cAMP), the allosteric activator of the cAMP receptor protein (CRP), master regulator of carbon utilization.
The resulting reduction in cAMP concentration, which is independent of carbon source, decreases transcription of CRP-cAMP-activated carbon utilization genes, hinders carbon source uptake, and restricts metabolism, rendering wild-type bacteria phenotypically CRP−. A cAMP-independent allele of CRP overcame the transcriptional, uptake, and metabolic restrictions caused by cytoplasmic Mg2+ starvation and significantly increased transcription of the glucose uptake gene when S. Typhimurium was inside murine macrophages.
The reduced preference for glucose exhibited by S. Typhimurium inside macrophages reflects that transcription of the glucose uptake gene requires higher amounts of active CRP-cAMP than transcription of uptake genes for preferred carbon sources, such as gluconate and glycerol. By reducing CRP-cAMP activity, low cytoplasmic Mg2+ alters carbon source preference, adjusting metabolism and growth."
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