A new antibiotic compound can clear infection of multi-drug resistant gonorrhea in mice with a single oral dose, according to a new study led by researchers at Penn State and Emory.
Like other antibiotics, this one targets the ribosome, the factories that generate proteins in bacterial (and human) cells. But it does so at a site that is different from other antibiotics. This one interferes with the process of trans-translation, which bacteria use to rescue their ribosomes out of rough spots.
Zachary Aron, director of chemistry at Microbiotix, is the first author of the paper, and the compound is called MBX-4132. It is also active against other Gram-positive bacteria, including tuberculosis and Staph aureus, and the company says it will continue to optimize it.
At Emory, Dunham’s lab used cryo-electron microscopy to produce high-resolution images of the compound as it binds to the bacterial ribosome — see below.
“A derivative of MBX-4132 binds to a location on the ribosome that is different from all known antibiotic binding sites,” Dunham says. “The new drug also displaces a region of a ribosomal protein that we think could be important during the normal process of trans-translation. Because trans-translation only occurs in bacteria and not in humans, we hope that the likelihood of the compound affecting protein synthesis in humans is greatly reduced, a hypothesis strongly supported by the safety and selectivity studies performed by Microbiotix.”
Before 2020 and the COVID-19 pandemic, concern among infectious disease specialists was rising about Candida auris, an emerging fungal pathogen that is often drug-resistant and difficult to eradicate from hospitals.
Many people know Candida can cause mouth or vaginal infections and diaper rashes. According to the CDC, Candida also can cause invasive infections in the bloodstream, particularly in hospital or nursing home patients with weakened immune systems. About 30 percent of patients with an invasive Candida infection die – and C. auris is just one particularly hardy variety.
Emory Antibiotic Resistance Center director David Weiss and colleagues have identified a combination of existing antifungal drugs (micafungin and amphotericin B) with enhanced activity against C. auris when used together. The results – in vitro only, so far — were published in a letter to The Lancet Microbe. Postdoctoral fellow Siddharth Jaggavarapu was the first author. Weiss reports his team continues to investigate combination approaches against C. auris.
The resistance of bacteria to antibiotics is a global challenge that has been exacerbated by the financial burdens of bringing new antibiotics such as the Metronidazole 500mg tablets to market and an increase in serious bacterial infections as a result of the COVID-19 pandemic.
Biomedical engineering researchers at Georgia Tech and Emory are tackling the problem of antibiotic resistance not by creating new drugs, but by enhancing the safety and potency of ones that already exist.
Aminoglycosides are antibiotics used to treat serious infections caused by pathogenic bacteria like E. coli or Klebsiella. Bacteria haven’t developed widespread resistance to aminoglycosides, as compared to other types of antibiotics.These antibiotics are used sparingly by doctors, in part because of the toxic side effects they can sometimes cause.
In research published in the journal PLOS One, Christopher Rosenberg, Xin Fang and senior author Kyle Allison demonstrated that lower doses of aminoglycosides could be used to treat bacteria when combined with specific metabolic sugars. Low concentrations of antibiotics alone often cannot eliminate dormant, non-dividing bacterial cells, but the researchers hypothesized based on a past study that combining aminoglycosides with metabolites such as glucose, a simple sugar, or mannitol, a sugar alcohol often used as sweetener, could stimulate antibiotic uptake.
The authors tested these treatment combinations against Gram-negative pathogens E. coli, Salmonella and Klebsiella. The results showed that aminoglycoside-metabolite treatment significantly reduced the concentration of antibiotic needed to kill those pathogens. The authors also demonstrated that this treatment combination did not increase bacterial resistance to aminoglycosides and was effective in treating antibiotic-tolerant biofilms, which are bacterial communities that act as reservoirs of infection.
The triple play is this — on her blog, Emma has discussed how she has to deal with antibiotic resistance. Emory Antibiotic Resistance Center director David Weiss’ lab has published a lot on colistin: how it’s a last-resort drug because of side effects, and how difficult-to-detect resistance to it is spreading. Emma has some personal experience with colistin that for me, brought the issue closer. Read more
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.
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.
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.
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.
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.
“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.
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.
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
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 withÂ 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-diarrhealÂ Immodium, can make bacteria sensitive toÂ 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 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. SheÂ and her colleagues have been investigatingÂ compounds that can disruptÂ biofilms, thusÂ enhancingÂ antibiotic activity. More at eScienceCommonsÂ and at her lab’s site.
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 Emoryâ€™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