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ESBL E.coli

ESBL E.coli are E.coli that produce an enzyme that can destroy commonly used antibiotics. This leaves few antibiotic options available for treatments of these infections. In 2017, an estimated 1.2 billion in attributable healthcare costs, 197,400 cases, and 9,100 estimated deaths in the US.

THE PATHOGEN

Escherichia coli (E. coli) are Gram-negative, rod-shaped bacteria commonly found in the intestines of people and animals. E. coli are a large and diverse group of bacteria found in the environment, food, and the intestines of people and animals. While most strains of E.coli are harmless, others can make you sick. Some kinds of E.coli cause diarrhea, others cause urinary tract infections, respiratory illness and pneumonia. ESBL E.coli produce an enzyme (Extended-Spectrum β-Lactamase) which are capable of breaking down and destroying commonly used antibiotics such as penicillins and cephalosporins, which makes these drugs unable to treat infections. One particular ESBL enzyme, CTX-M appears to be spreading in the United States and around the world. Shiga toxin-producing E.coli (STEC) cause disease by making a toxin called Shiga toxin. The most common strain producing this toxin is E.coli 0157, which is usually the culprit behind outbreaks. Enterotoxigenic E.coli (ETEC) are the leading cause of diarrheal disease, producing two toxins: ST and LT. These toxins stimulate the lining of the intestines to secrete excess liquid, which produces diarrhea.

ESBL E.coli infections

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STEC infections vary in their symptoms, but often include severe stomach cramps, diarrhea (often bloody) and vomiting. In severe cases, hemolytic uremic syndrome can occur - loss of platelets, low blood cell count and kidney failure. HUS is more common in the elderly and very young children. ETEC infections can cause profuse watery diarrhea and abdominal cramping. Less commonly fever, nausea, muscle aches, and bloating can occur. 


ESBL E.coli Antibiotic Resistance 

ESBL E.coli produce the extended spectrum β-Lactamase that can destroy penicillins and cephalosporins, making these drugs ineffective. Carbapenems are one of the few remaining antibiotics that can treat ESBL infections, but resistance enzymes that can destroy these antibiotics are already on the rise. Mutations in the bacteria that either reduce the ability of antibiotics to enter the bacterial cell (outer membrane porin loss) or increase the pumping of the antibiotic out of the cell (efflux pump activation) are both effective resistance mechanisms. Additionally, E.coli can acquire carbapenmases - enzymes that can destroy carbapenem - such as NDM-1.

 

NEW SEPSIS THERAPEUTIC TARGET

PHLPP1, a phosphatase found to act on many immune cell genes specifically acts on STAT1, and acts to control inflammation. Removing the enzyme PHLPP1 from mice improved survival outcomes in a mouse model of sepsis compared to WT controls. Selective inhibitors of PHLPP1 may form the basis for new anti-sepsis therapeutics.

Click here to read more about PHLPP1