Update on SIV remission studies

Recently presented insights on how an antibody used to treat intestinal diseases can suppress Read more

Granulins treasure not trash - potential FTD treatment strategy

Granulins are of interest to neuroscientists because mutations in the granulin gene cause frontotemporal dementia (FTD). However, the functions of granulins were previously Read more

Blood vessels and cardiac muscle cells off the shelf

How to steer induced pluripotent stem cells into becoming endothelial cells, which line blood Read more

antibiotic resistance

Meningitis bacteria adapt to STI niche — again?

A new paper in PNAS from Emory scientists highlights a neat example of bacterial evolution and adaptation related to sexually transmitted infections. Neisseria meningitidis, a bacterium usually associated with meningitis and sepsis, sometimes appears in the news because of cases on college campuses or other outbreaks.

The N meningitidis bacteria causing a recent cluster of sexually transmitted infections in Columbus, Ohio and other US cities have adapted to the urogenital environment, an analysis of their DNA shows.

Update: May 2016 Clinical Infectious Diseases paper on the same urethritis cluster.

Genetic changes make this clade look more like relatives that are known to cause gonorrhea. Some good news is that these guys are less likely to cause meningitis because they have lost their outer capsule. They have also gained enzymes that help them live in low oxygen.

The DNA analysis helps doctors track the spread of this type of bacteria and anticipate which vaccines might be protective against it. Thankfully, no alarming antibiotic resistance markers are present (yet) and currently available vaccines may be helpful. Full press release here, and information about meningococcal disease from the CDC here.

This looks like a well-worn path in bacterial evolution, since N. gonorrhoeae is thought to have evolved from N. meningitidis and there are recent independent examples of N. meningitidis adapting to the urogenital environment. 

Posted on by Quinn Eastman in Immunology Leave a comment

Retaining the resistance: MCR-1, colistin + lysozyme

If you’ve been following the news about antibiotic resistant bacteria, you may have heard about a particularly alarming plasmid: MCR-1. A plasmid is a circle of DNA that is relatively small and mobile – an easy way for genetic information to spread between bacteria. MCR-1 raises concern because it provides bacteria resistance against the last-resort antibiotic colistin. The CDC reports MCR-1 was found in both patients and livestock in the United States this summer.
David Weiss, director of Emory’s Antibiotic Resistance Center, and colleagues have a short letter in The Lancet Infectious Diseases showing that MCR-1 also confers resistance to an antimicrobial enzyme produced by our bodies called lysozyme. MCR-1-containing strains were 5 to 20 times less susceptible to lysozyme, they report.
This suggests that the pressure of fighting the host immune system may select for MCR-1 to stick around, even in the absence of colistin use, the authors say.
While the findings are straightforward in bacterial culture, Weiss cautions that there is not yet evidence showing that this mechanism occurs in live hosts. For those that really want to get alarmed, he also calls attention to a recent Nature Microbiology paper describing a hybrid plasmid with both MCR-1 and resistance to carbapenem, another antibiotic.

Read more

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Fooling the test: antibiotic resistant bacteria that look susceptible

A diagnostic test used by hospitals says a recently isolated strain of bacteria is susceptible to the “last resort” antibiotic colistin. But the strain actually ignores treatment with colistin, causing lethal infections in animals.

Through heteroresistance, a genetically identical subpopulation of antibiotic-resistant bacteria can lurk within a crowd of antibiotic-susceptible bacteria. The phenomenon could be causing unexplained treatment failures in the clinic and highlights the need for more sensitive diagnostic tests, researchers say.

In Nature Microbiology (published online Monday, May 9), scientists led by David Weiss, PhD, describe colistin-heteroresistant strains of Enterobacter cloacae, a type of bacteria that has been causing an increasing number of infections in hospitals around the world.

“Heteroresistance has been observed previously and its clinical relevance debated,” Weiss says. “We were able to show that it makes a difference in an animal model of infection, and is likely to contribute to antibiotic treatment failures in humans.”

Weiss is director of the Emory Antibiotic Resistance Center and associate professor of medicine (infectious diseases) at Emory University School of Medicine and Emory Vaccine Center. His laboratory is based at Yerkes National Primate Research Center. The co-first authors of the paper are graduate students Victor Band and Emily Crispell.

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An effective alternative to fecal transplant for C. difficile?

Bacterial spores in capsules taken by mouth can prevent recurrent C. difficile infection, results from a preliminary study suggest.

Clostridium difficile is the most common hospital-acquired infection in the United States and can cause persistent, sometimes life-threatening diarrhea. Fecal microbiota transplant has shown promise in many clinical studies as a treatment for C. difficile, but uncertainty has surrounded how such transplants should be regulated and standardized. Also, the still-investigational procedure is often performed by colonoscopy, which may be difficult for some patients to tolerate.

The capsule study, published Monday in Journal of Infectious Diseases, represents an important step in moving away from fecal microbiota transplant as a treatment for C. difficile, says Colleen Kraft, MD, assistant professor of pathology and laboratory medicine and medicine (infectious diseases) at Emory University School of Medicine.

Kraft and Tanvi Dhere, MD, assistant professor of medicine (digestive diseases) have led development of the fecal microbiota transplant program at Emory. They are authors on the capsule study, along with investigators from Mayo Clinic, Massachusetts General Hospital, Miriam Hospital (Rhode Island), and Seres Therapeutics, the study sponsor.

While this study involving 30 patients did not include a control group, the reported effectiveness of 96.7 percent compares favorably to published results on antibiotic treatment of C. difficile infection or fecal microbial transplant. Read more

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Rescuing existing antibiotics with adjuvants

One of the speakers at Thursday’s Antibiotic Resistance Center symposium, Gerald Wright from McMaster University, made the case for fighting antibiotic resistance by combining known antibiotics with non-antibiotic drugs that are used to treat other conditions, which he called adjuvants.

As an example, he cited this paper, in which his lab showed that loperamide, known commercially as the anti-diarrheal Immodium, can make bacteria sensitive to tetracycline-type antibiotics.

Wright said that other commercial drugs and compounds in pharmaceutical companies’ libraries could have similar synergistic effects when combined with existing antibiotics. Most drug-like compounds aimed at human physiology follow “Lipinski’s rule of five“, but the same rules don’t apply to bacteria, he said. What might be a more rewarding place to look for more anti-bacterial compounds? Natural products from fungi and plants, Wright proposed.

“I made a little fist-pump when he said that,” says Emory ethnobotanist Cassandra Quave, whose laboratory specializing in looking for anti-bacterial activities in medicinal plants.

Medical thnobotanist Cassandra Quave collecting plant specimens in Italy.

Medical ethnobotanist Cassandra Quave collecting plant specimens in Italy

Indeed, many of the points he made on strategies to overcome antibiotic resistance could apply to Quave’s approach. She and her colleagues have been investigating compounds that can disrupt biofilms, thus enhancing antibiotic activity. More at eScienceCommons and at her lab’s site.

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Galectins defend against bacterial wolves in sheeps’ clothing

To prevent auto-immune attack, our bodies avoid making antibodies against molecules found on our own cells. That leaves gaps in our immune defenses bacteria could exploit. Some of those gaps are filled by galectins, a family of proteins whose anti-bacterial properties were identified by Emory scientists.

In the accompanying video, Sean Stowell, MD, PhD and colleagues explain how galectins can be compared to sheep dogs, which are vigilant in protecting our cells (sheep) against bacteria that may try to disguise themselves (wolves).

The video was produced to showcase the breadth of research being conducted within Emory’s Antibiotic Resistance Center. Because of their ability to selectively target some kinds of bacteria, galectins could potentially be used as antibiotics to treat infections without wiping out all the bacteria in the body. Read more

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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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