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Category Archives: Sci Tech Daily

New Strategy Makes Bacteria More Vulnerable to Antibiotics

New Strategy Makes Bacteria More Vulnerable to Antibiotics

Scientists at MIT have discovered a way to make bacteria more vulnerable to a class of antibiotics known as quinolones, which include ciprofloxacin and are often used to treat infections such as Escherichia coli and Staphylococcus aureus.

The new strategy overcomes a key limitation of these drugs, which is that they often fail against infections that feature a very high density of bacteria. These include many chronic, difficult-to-treat infections, such as Pseudomonas aeruginosa, often found in the lungs of cystic fibrosis patients, and methicillin-resistant Staphylococcus aureus (MRSA).

“Given that the number of new antibiotics being developed is diminishing, we face challenges in treating these infections. So efforts such as this could enable us to expand the efficacy of existing antibiotics,” says James Collins, the Termeer Professor of Medical Engineering and Science in MIT’s Institute for Medical Engineering and Science (IMES) and Department of Biological Engineering and the senior author of the study.

Arnaud Gutierrez, a former MIT postdoc, and Saloni Jain, a recent Boston University PhD recipient, are the lead authors of the study, which appears in the December 7 online edition of Molecular Cell.

Overcoming bacterial defenses

Bacteria that have become tolerant to a drug enter a physiological state that allows them to evade the drug’s action. (This is different from bacterial resistance, which occurs when microbes acquire genetic mutations that protect them from antibiotics.) “Tolerance is not well-understood, and we don’t have the means to circumvent it or overcome it,” Collins says.

In a study published in 2011, Collins and his colleagues found that they could increase the ability of antibiotics known as aminoglycosides to kill drug-tolerant bacteria by delivering a type of sugar along with the drug. The sugar helps to boost the metabolism of the bacteria, making it more likely that the microbes will undergo cell death in response to the DNA damage caused by the antibiotic.

However, aminoglycosides can have serious side effects, so they are not widely used. In their new study, Collins and his colleagues decided to explore whether they could use a similar approach to boost the effectiveness of quinolones, a class of antibiotics used more often than aminoglycosides. Quinolones work by interfering with bacterial enzymes called topoisomerases, which help with DNA replication and repair.

With quinolones, the researchers found that it wasn’t enough to add just sugar; they also had to add a type of molecule known as a terminal electron acceptor. Electron acceptors play an essential role in cellular respiration, the process that bacteria use to extract energy from sugar. In cells, the electron acceptor is usually oxygen, but other molecules, including fumarate, an acidic organic compound that is used as a food additive, can also be used.

In tests in high-density bacterial colonies grown in a lab dish, the researchers found that delivering quinolones along with glucose and fumarate could eliminate several types of bacteria, including Pseudomonas aeruginosa, Staphylococcus aureus, and Mycobacterium smegmatis, a close relative of the bacterium that causes tuberculosis.

“If you simply add a carbon source like glucose, that’s not enough to enable the quinolone to kill. If you simply add oxygen, or another terminal electron acceptor, that by itself is not enough to cause killing either. But if you combine the two, you can eradicate the tolerant infection,” Collins says.

Metabolic state

The findings suggest that high-density bacterial infections rapidly consume nutrients and oxygen from their environment, which then provokes them to enter a starvation state that helps them to survive. In this state, they greatly reduce their metabolic activity, which allows them to avoid the cell death pathway that is normally triggered when DNA is damaged by antibiotics.

“This finding highlights that the metabolic state of the bug significantly influences how the antibiotic will impact the bug. And, for the antibiotic to be effective as a killing agent, it requires downstream cellular respiration as part of the process,” Collins says.

The researchers now hope to test this approach in bacterial infections in animals, and they are also exploring how to best deliver the drug combination for different types of infections. A topical treatment could work well for Staphylococcus aureus infections, while an inhaled version could be used to treat Pseudomonas aeruginosa infections of the lungs, Collins says.

Collins also hopes to test this approach with other types of antibiotics, including the class that includes penicillin and ampicillin.

“This study encourages work to find new ways to stimulate bacterial respiration and thereby enhance the production of reactive oxygen (or even non-oxygen) species during antibiotic treatment, for better eradication of bacterial pathogens, particularly those having low metabolic activity that may render them tolerant to antimicrobials,” says Karl Drlica, a professor at the Public Health Research Institute at Rutgers New Jersey Medical School, who was not involved in the research.

The research was funded by the Defense Threat Reduction Agency, the Broad Institute of MIT and Harvard, and a gift from Anita and Josh Bekenstein.

This article was published in Scitechdaily dated ‘Dec. 07, 2017’

Small-Molecule Inhibitor NGI-1 Blocks Zika and Dengue Viruses

Small-Molecule Inhibitor NGI-1 Blocks Zika and Dengue Viruses

A new study published in Cell Reports details how a small-molecule inhibitor tested by researchers at Yale and Stanford may be the answer to blocking the spread of harmful mosquito-borne pathogens, including Zika and dengue viruses.

The molecule, dubbed NGI-1, was identified by co-author Joseph Contessa, M.D., an associate professor of therapeutic radiology and of pharmacology at Yale School of Medicine. In collaboration with Stanford researchers, Contessa’s team investigated whether NGI-1 could prevent replication of the viruses in host cells.

In experiments, the research team infected human cells with either dengue or Zika viruses and treated the cells with NGI-1. They found that the molecule treatment significantly limited replication of the viruses as well as infection in cells. Their experiments proved their theory that NGI-1 worked by specifically targeting an enzyme within the cells that the viruses use to copy themselves.

Additionally, the research team found that while NGI-1 restricted viral activity, it did not affect other cell functions, which suggests low risk of toxicity or side effects from the molecule treatment.

The researchers noted that because the molecule targets an enzyme common to host cells, instead of the individual viruses, the findings apply to other viruses of the same type.

“Our report shows, for the first time, that we can use a small-molecule inhibitor to block infection by the flaviviridae family of viruses,” Contessa said. “This group includes Zika, dengue, West Nile, and yellow fever viruses, which affect hundreds of millions of people per year worldwide.”

The team plans to develop the molecule into a drug to treat the viral infections, which don’t currently have any approved antiviral therapy. Such treatment would not only benefit infected individuals, but also potentially help stem the spread of outbreaks, said Contessa.

Other authors on the study are Andreas S. Puschnik, Caleb D. Marceau, Yaw Shin Ooi, Karim Majzoub, Natalia Rinis, and Jan E. Carette. Contessa is listed on a provisional patent as an inventor for use of the small molecule as an inhibitor.

The study was funded by the National Institutes of Health, David and Lucile Packard Foundation, Stanford Graduate Fellowship, and Boehringer Ingelheim Fonds.

This article was published in Scitechdaily dated ‘Dec. 13, 2017’