Bacteria

Researchers Are Using Viruses to Make Superbugs Commit Suicide

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The gene-editing technology called CRISPR has its origins as a bacterial immune system against viruses, a feature which could be turned against them in the future.

By arming bacteriophage viruses with the tools to force bacteria into falling on their own swords, scientists hope we will be able to develop powerful new ways to defeat antibiotic resistant pathogens and perhaps even shape our body’s microflora.

Research presented at the CRISPR 2017 conference in the US described the progress that has been made in modifying viruses that target specific bacteria with genes that make the host’s enzymes cut into its own DNA.

Clustered regularly interspaced short palindromic repeats – CRISPR for short – are sequences of DNA made of a repeating codes that form a long palindrome.

Bacteria produce them as a kind of immune system against viruses called bacteriophages, slipping bits of the virus’s genes scavenged out of the environment into the repeating codes.

With the viral DNA stored away in CRISPR sequences, any future infections can be detected quickly and a CRISPR-associated system (or cas) enzyme can then use the sequence as a beacon, latching onto the infecting virus genes and either snipping them selectively or tearing them to shreds.

About 25 years ago, researchers realised this cut-and-paste system of CRISPR sequences and cas enzymes could be used in the lab to edit sequences artificially, and a new engineering toolkit was born.

The technology has been in the news quite a bit in recent years as advances have been made in applying it to cancer treatments and even eliminating HIV infections.

While it might not be without certain risks, CRISPR gene editing has sparked a something of a minor revolution.

Bringing it back to its roots and turning it into a weapon against its creators has a sense of serendipity about it.

“I see some irony now in using phages to kill bacteria,” said the chief scientific officer of Locus Biosciences, Rodolphe Barrangou, at the CRISPR 2017 conference.

Using bacteriophages as a form of therapy to treat infection isn’t all that new, with trials dating as far back as the 1920s.

The use of phages is appealing because they are far more specific than antibiotics, targeting only specific types of bacteria and therefore posing no risk to our own health. The viruses can also penetrate the coatings of sticky film bacteria produce for protection and adherence.

Russia experienced a fair degree of success with phage therapy behind its Iron Curtain during the Cold War, but unable to patent the naturally occurring viruses and with the bacteria quickly adapting, red tape and limitations in technology have made it far easier to focus on antibiotics in the west.

With looming epidemics of superbugs on the horizon, attention is returning to bacteriophages as ways to kill bacteria, and CRISPR has put a new spin on the old idea.

A spin-off company from North Carolina State University, Locus Biosciences is testing the limits of CRISPR technology, including giving bacteriophages CRISPR sequences containing codes for antibiotic resistance genes.

Targeting bacteria with the genes, the CRISPR sequence would form a target for the bacteria’s own cas enzymes, effectively blocking resistance or even prompting the bacteria into chewing up its own DNA and self-destructing.

In recent years our eyes have been opened to how complex our relationship is with bacteria in our environment, and how dull our tools are for dealing with them.

Variations in our gut microflora has been linked with everything from Parkinson’s disease to autism to obesity, suggesting the species of bacteria we harbour could have major ramifications on many aspects of our health.

With its razor-honed surgical precision, it’s possible the technology could one day be used to select specific strains of bacteria in our gut, deleting them from the ecosystem and allowing us to edit our microbiomes.

Given we’re practically at the dawn of both CRISPR technology and our grasp on the complexity behind our body’s bacterial ecosystems, we can only speculate for the time being.

As antibiotics slowly lose their shine it’s probably worth paying close attention to radical new solutions such as these.

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Vaginal Bacteria Have Been Found to Neutralise HIV Treatment

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A study on the vaginal bacteria of South African women has revealed that a certain type of bacteria is able to break down a common drug used for the prevention of HIV.

Annually, more than 1 million women are infected with human immunodeficiency virus (HIV). HIV infection rates among women are a major health concern, as HIV can be passed from mothers to their children during pregnancy, childbirth ,and breastfeeding.

“I believe this will change the way we approach HIV prevention studies in women,” lead researcher Nichole Klatt, from the University of Washington, told ScienceAlert.

The microbicide drug, tenofovir, is widely used to combat the spread of HIV, and works by inhibiting the process that allows HIV to replicate. While tenofovir routinely protects men against HIV infection, women using the same drug might not see the same results.

But what exactly does the vagina have to do with drug administration?

In Africa, tenofovir is being applied in a gel directly into the vagina. Taking a tablet isn’t always ideal in Sub-Saharan Africa, and the focus of prevention here is to stop the spread of HIV at the site of infection during sex.

Other studies have revealed that the vagina may contain bacteria that acts as a sort of ‘biological condom’, protecting against the infection of HIV and STIs.

To investigate the potentially negative effects these bacteria are having on tenofovir, Klatt and her team collected vaginal swabs from 688 South African women as they participated in a clinical trial into the efficiency of an intravaginal gel against HIV infection.

The team found that there were two major types of vaginal bacteria present in the sample group – one contained Lactobacillus, and the other contained Gardnerella vaginalis.

Of the two major types of vaginal bacteria, the women with non-lactobacillus bacteria had a reduction of HIV infection of only 18 percent, while those with Lactobacillus had a reduction in HIV infection rate of 61 percent when using the gel – a threefold increase in protection.

The scientists investigated further, and discovered that G. vaginalis could metabolise and breakdown the active form of the drug, rendering it useless in the fight against the spread of HIV.

“These data demonstrate that vaginal microbiota must be accounted for and to improve efficacy of HIV prevention, novel interventions to enhance Lactobacillus and decrease Gardnerella and other BV-associated bacteria are needed,” Klatt told ScienceAlert.

The scientists hope that the results will inform the ways in which the drug is administered based on the bacteria present in a patient’s vagina.

“We are now excited to be forging the way ahead in pharmacomicrobiomics studies in HIV and other diseases. Specifically, we are assessing other drugs that bacteria may interact with in the vagina, and the specific mechanisms underlying this,” says Klatt.

“We are also developing systems to assess drug-microbiota interactions in other diseases such as IBD and cancer, where mechanisms underlying variable drug efficacy are unknown.”

The research is published in Science.

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What You Need to Know About the Deadly ‘Superbug’ Infection Resistant to All FDA-Approved Antibiotics

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PHOTO: An illustration of a group of carbapenem-resistant Enterobacteriaceae bacteria. The image was based on scanning electron micrographic imagery.

The rise of drug-resistant bacterial “superbugs” have been a concern of public health officials for years, but the U.S. Centers for Disease Control and Prevention has reported a worse-case scenario — a woman with a bacterial infection that was resistant to all FDA-approved treatments.

A Nevada woman died in September after being infected with type of drug-resistant bacteria called Klebsiella pneumonaiae that was resistant to all antibiotics available in the U.S., the CDC reported on Friday.

The woman was in her 70’s when she arrived at hospital in August 2016 with signs of sepsis. She had been in India years before and had been treated for a broken leg and bone infection, according to the CDC. After doing tests, her doctors found the bacteria — which belonged to a class of drug-resistant bugs called carbapenem-resistant Enterobacteriaceae (CRE) — were resistant to all forms of FDA-approved antibiotics. The patient died in September after going into septic shock, according to the CDC.

The woman’s extremely rare infection has focused attention on the increasing problems surrounding these drug-resistant infections and the lack of antibiotics available to treat them.

Fewer New Antibiotics Being Developed

No matter how effective an antibiotic is at killing bacteria, new drugs will be needed as the bacteria mutate and grow more resistant to the existing drugs.

“Antibiotic resistance occurs as part of a natural evolution process, it can be significantly slowed but not stopped,” the CDC notes on its website. “New antibiotics will always be needed to keep up with resistant bacteria as well as new diagnostic tests to track the development of resistance.”

However, the number of drug applications for novel antibiotics being developed by pharmaceutical companies have been dropping steadily over the last three decades, according to the CDC.

From 1980 to 1984, there were nearly 20 FDA drug applications approved for new antibiotics, but from 2005 to 2009, there were fewer than five applications approved, according to the CDC.

In 2013, the CDC said developing new antibiotics and new diagnostic tests was one of its four core actions to stop antibiotic-resistant infections from increasing.

CRE Infections Are an ‘Urgent Threat’

In 2013, CDC characterized CRE infections as an “urgent” threat, meaning the bacteria is an “immediate public health threat that requires urgent and aggressive action.”

The bacteria cause 9,000 drug-resistant infections per year and 600 related deaths, according to the CDC.

While most drug-resistant CRE bacteria are still susceptible to one or more antibiotic, in the infection of the woman in her 70’s reported by the CDC, the bacteria was resistant to all FDA-approved antibiotics, an extremely rare event.

CRE include common bacteria such as E.coli and Klebsiella bacteria.

Doctors Can Attempt to Treat Even Drug-Resistant Infections

When a patient has a drug-resistant bacteria, doctors will sometimes have to use harsher antibiotics or high dosages in order to try and fight the infection.

If a patient has a drug-resistant infection, doctors will work with a lab to test different doses of various antibiotics in an effort to overwhelm and kill the bacteria, said Dr. William Schaffner, an infectious disease expert at Vanderbilt University Medical Center.

However, antibiotics can be taxing on the patient, especially if they are older and with underlying medical conditions.

“This is the kind of calculation you do with every patient,” Schaffner said. “Patients with underlying illnesses present a certain kind of challenge.”

The CDC authors reported that an intravenous version of an antibiotic called fosfomycin is available in other countries but not for use in the U.S. It’s unclear if the patient’s doctors attempted to get an FDA exemption to use the drug and treat the patient.

Long Exposure to Antibiotics and Long Hospital Stays Can Be Dangerous

While this recently reported case is frightening, it is also unusual. The patient had been in and out of hospitals in India for two years after fracturing the large femur bone in her leg and developing a bone infection.

Long hospitals stays, especially in India, and exposure to different antibiotics can increase the likelihood of eventually developing a drug-resistant bacterial infection. As travel around the globe is becoming easier, it’s increasingly important for doctors to find out where their patients may have acquired an infection, Schaffner said.

“India has a notorious reputation for this [type of bacteria,]” he noted. “Travel-related questions are becoming much more important … and just reinforce that we are a very small world.”

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Scientists are genetically engineering Salmonella to destroy brain tumours

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Salmonella is commonly linked to fevers and food poisoning, and generally speaking, it isn’t good news at all for your body. But scientists have come up with an exception: a genetically engineered form of Salmonella bacteria that can eat away at cancer tumours.

The modified bacteria target tumours in the brain rather than seeking out the human gut where Salmonella usually causes damage – and the technique could lead to  a highly targeted technique of fighting one of the worst types of cancer there is.

Researchers from Duke University gave the treatment to rats with the aggressive brain cancer glioblastoma, and saw significant increases in lifespans, with 20 percent of the rodents surviving an extra 100 days compared to control animals – the equivalent of 10 years in human terms.

“Since glioblastoma is so aggressive and difficult to treat, any change in the median survival rate is a big deal,” says one of the team, Johnathan Lyon.

“And since few survive a glioblastoma diagnosis indefinitely, a 20 percent effective cure rate is phenomenal and very encouraging.”

salmonella-close-lookBacteria (pink) take hold of cancer cells (blue). Credit: Duke University

It’s a promising direction of study, since survival rates of humans with this cancer are pretty bleak. Only about 30 percent of patients with glioblastoma live for more than two years after diagnosis.

Part of what makes it so hard to treat is that the tumours hide behind the blood-brain barrier, which separates the circulating blood from the brain’s own fluid.

Conventional drugs can’t easily reach through this membrane, so a more targeted approach is needed to stop glioblastoma from thriving.

To achieve this, the researchers used a genetically adjusted and detoxified form of Salmonella typhimurium, modified to be deficient in a crucial organic compound called purine.

Glioblastoma tumours are an abundant source of this enzyme, which induces the bacteria to seek out the cancer cells to get the purine that they need.

And when the bacteria get to the tumours, two more genetic tweaks kick into action.

Because cancerous cells multiply so quickly, oxygen is scarce inside and around tumours. Knowing this, the scientists coded their Salmonella to produce two proteins called Azurin and p53 in the presence of low levels of oxygen.

These compounds instruct the cancer cells to effectively self-destruct, so the end result is like a genetically-coded guided missile, seeking out the tumour and blitzing cancerous cells when it arrives.

The researchers say the technique is much more accurate than surgery, and because the bacteria are otherwise detoxified, there should be no damaging side effects for the patient.

Of course, having success with a group of rats is no guarantee that the treatment will translate to the human body, but the researchers are hopeful that the technique can be developed to treat cancer patients in the future.

The first step is to get that 20 percent success rate up. Based on initial tests, the 80 percent of cases where the treatment had no effect could be down to the tumour cells outpacing the bacteria, or inconsistencies in the Salmonella‘s penetration in the body.

“It might just be a case of needing to monitor the treatment’s progression and provide more doses at crucial points in the cancer’s development,” says Lyon.

“However, this was our first attempt at designing such a therapy, and there is some nuance to the specific model we used, thus more experiments are needed to know for sure.”

The research has been published in Molecular Therapy Oncolytics.

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