Two items relevant to long COVID

One of the tricky issues in studying in long COVID is: how widely do researchers cast their net? Initial reports acknowledged that people who were hospitalized and in intensive care may take a while to get back on their feet. But the number of people who had SARS-CoV-2 infections and were NOT hospitalized, yet experienced lingering symptoms, may be greater. A recent report from the United Kingdom, published in PLOS Medicine, studied more than Read more

All your environmental chemicals belong in the exposome

Emory team wanted to develop a standard low-volume approach that would avoid multiple processing steps, which can lead to loss of material, variable recovery, and the potential for Read more

Signature of success for an HIV vaccine?

Efforts to produce a vaccine against HIV/AIDS have been sustained for more than a decade by a single, modest success: the RV144 clinical trial in Thailand, whose results were reported in 2009. Now Emory, Harvard and Case Western Reserve scientists have identified a gene activity signature that may explain why the vaccine regimen in the RV144 study was protective in some individuals, while other HIV vaccine studies were not successful. The researchers think that this signature, Read more

antibiotic resistance

Nudging physician behavior on antibiotic orders

Part of the problem of antibiotic resistance involves physicians’ habits. Doctors are used to prescribing antibiotics in certain situations, even when they may be inappropriate or when alternatives may be best. However, they may be susceptible to “nudges”, even if health care organization policies don’t formally restrict their choices. Former White House regulatory policy guru Cass Sunstein has written several books on this concept.

In March 2015, MD/PhD student Kira Newman and colleagues published a study in Journal of General Internal Medicine that has some bearing on this idea, although it doesn’t address antibiotic resistance directly:

Yelp for Prescribers: a Quasi-Experimental Study of Providing Antibiotic Cost Data and Prescription of High-Cost Antibiotics in an Academic and Tertiary Care Hospital.

The authors describe a shift involving the Emory University hospital electronic health record and order entry system. When a patient has systemic or urinary tract bacterial infection, the system shows a table of antibiotic sensitivity data alongside blood or urine culture results.

Beginning in May 2010, cost category data for antibiotics were added. Explicit numbers were not included – too complicated. Instead, the information was coded in terms of $ to $$$$. For the year after the change, the authors report a 31 percent reduction in average cost per unit of antibiotics prescribed. Read more

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Adaptive mutation mechanism may drive some forms of antibiotic resistance

Evolutionary theory says mutations are blind and occur randomly. But in the controversial phenomenon of adaptive mutation, cells can peek under the blindfold, increasing their mutation rate in response to stress.

Scientists at Winship Cancer Institute, Emory University have observed that an apparent “back channel” for genetic information called retromutagenesis can encourage adaptive mutation to take place in bacteria.

The results were published Tuesday, August 25 in PLOS Genetics.

“This mechanism may explain how bacteria develop resistance to some types of antibiotics under selective pressure, as well as how mutations in cancer cells enable their growth or resistance to chemotherapy drugs,” says senior author Paul Doetsch, PhD.

Doetsch is professor of biochemistry, radiation oncology and hematology and medical oncology at Emory University School of Medicine and associate director of basic research at Winship Cancer Institute. The first author of the paper is Genetics and Molecular Biology graduate student Jordan Morreall, PhD, who defended his thesis in April.

Retromutagenesis resolves the puzzle: if cells aren’t growing because they’re under stress, which means their DNA isn’t being copied, how do the new mutants appear?

The answer: a mutation appears in the RNA first. Read more

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All the boulders at the same time

Emory is preparing to launch a center devoted to antibiotic resistance. On Wednesday, Arjun Srinivasan, one of the CDC’s point people for antibiotic use and hospital acquired infections, kicked off the preparations with a talk on the multifaceted nature of this problem.

Without attempting to cover everything related to antibiotic resistance (that would take a book — or several), I will note in an upcoming post how Emory and partners such as Children’s Healthcare of Atlanta already have begun assembling many of the necessary tools.

Tackling antibiotic resistance has to take into account the habits of physicians, the expectations of patient, improved surveillance and antibiotic overuse in agriculture, as well as research on new antibiotics and detecting dangerous bacteria. In short, it’s both a science and policy issue — captured well by the documentary Resistance.

At the end of his talk, Srinivasan made a remark that brought this home for me, saying “We just have to push all the boulders up the hill at the same time” in response to a question about balancing effort on science vs policy. Allusions to Sisyphus!

Yet he provided some hope too, highlighting a recent CDC study that models how a coordinated response to antibiotic resistance in health care facilities could substantially cut infections. Read more

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Antibiotic resistance enzyme caught in the act

Resistance to an entire class of antibiotics – aminoglycosides — has the potential to spread to many types of bacteria, according to new biochemistry research.

A mobile gene called NpmA was discovered in E. coli bacteria isolated from a Japanese patient several years ago. Global spread of NpmA and related antibiotic resistance enzymes could disable an entire class of tools doctors use to fight serious or life-threatening infections.

Using X-ray crystallography, researchers at Emory made an atomic-scale snapshot of how the enzyme encoded by NpmA interacts with part of the ribosome, protein factories essential for all cells to function. NpmA imparts a tiny chemical change that makes the ribosome, and the bacteria, resistant to the drugs’ effects.

The results, published in PNAS, provide clues to the threat NpmA poses, but also reveal potential targets to develop drugs that could overcome resistance from this group of enzymes.

First author of the paper is postdoctoral fellow Jack Dunkle, PhD. Co-senior authors are assistant professor of biochemistry Christine Dunham, PhD and associate professor of biochemistry Graeme Conn, PhD. Read more

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Odd couples and persistence

When doctors treat disease-causing bacteria with antibiotics, a few bacteria can survive even if they do not have a resistance gene that defends them from the antibiotic. These rare, slow-growing or hibernating cells are called “persisters.”

Microbiologists see understanding persistence as a key to fighting antibiotic resistance and possibly finding new antibiotics. Persistence appears to be regulated by constantly antagonistic pairs of proteins called toxin-antitoxins.

Basically, the toxin’s job is to slow down bacterial growth by interfering with protein production, and the antitoxin’s job is to restrain the toxin until stress triggers a retreat by the antitoxin. Some toxins chew up protein-encoding RNA messages docked at ribosomes, but there are a variety of mechanisms. The genomes of disease-causing bacteria are chock full of these battling odd couples, yet not much was known about how they work in the context of persistence.

Biochemist Christine Dunham reports that several laboratories recently published papers directly implicating toxin-antitoxin complexes in both persistence and biofilm formation. Her laboratory has been delving into how the parts of various toxin-antitoxin complexes interact.HigBA smaller

BCDB graduate student Marc Schureck and colleagues have determined the structure of a complex of HigBA toxin-antitoxin proteins from Proteus vulgaris bacteria via X-ray crystallography. The results were recently published in Journal of Biological Chemistry.

While Proteus vulgaris is known for causing urinary tract and wound infections, the HigBA toxin-antitoxin pair is also found in several other disease-causing bacteria such as V. cholera, P. aeruginosa, M. tuberculosis, S. pneumoniae etc.

“We have been directly comparing toxin-antitoxin systems in E. coli, Proteus and M. tuberculosis to see if there are commonalities and differences,” Dunham says.

The P. vulgaris HigBA structure is distinctive because the antitoxin HigA does not wrap around and mask the active site of HigB, which has been seen in other toxin-antitoxin systems. Still, HigA clings onto HigB in a way that prevents it from jamming itself into the ribosome.

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