Drug resistant bacterial infections are the cause of death of about 700,000 people each year. Combating such drug resistant bacteria is important to the future of medical research. In a major step toward it, the life scientists at UCLA have found that combinations of three different antibiotics can overcome bacteria’s resistance to antibiotics. The report on the study was published recently in the journal Royal Society Interface. It reveals that this combination seem to work even if none of the three antibiotics on their own”or even two of the three together”is effective.

As a part of this study, E.coli was grown in a laboratory and the samples were then treated combinations of one, two and three antibiotics from a group of 14 drugs. The aim was to study how effective is every single combination of this drug to kill the bacteria. The biologists found that some combinations were successful is killing 100% of the bacteria, including 94 of the 364 three-drug groupings the researchers tested.

Pamela Yeh, the paper’s senior author and a UCLA assistant professor of ecology and evolutionary biology opined that the success rate could have been even higher if higher doses of the drugs were tested by the researchers.

A sophisticated framework created by Elif Tekin, the paper’s lead author and a UCLA graduate student, enabled the scientists in determining when adding a third antibiotic was producing new desired effects that couldn’t be achieved by combinations of just two drugs. Tekin opined that three antibiotics combination changes the dynamic. So far scientists didn’t explore the idea of three-drug combinations, but this study shows that it can have really beneficial effects.

Not all antibiotics work the same way – all have their own mechanism to fight bacteria. For example: one class, which includes amoxicillin, kills bacteria by preventing them from making cell walls. There is another class which disrupts the tightly coiled DNA of bacteria and the one suppresses their ability to make proteins. There has been little research in the past which explored the effect of combinations of three antibiotics on bacteria. The recent study reveals that the effect could be more potent together than any two of them.

According to Van Savage, a co-author of the paper and a UCLA associate professor of ecology and evolutionary biology and of biomathematics, there is a general tendency among people that there is no need to understand interactions beyond pairs. But, this research reveals that that isn’t the case always. In order to determine which group of antibiotic would be most effective, combination of techniques from biology and mathematics were applied by the researchers.

Yeh said it is important to choose the three antibiotics systematically and rationally. This research also found that sometimes adding a third antibiotic makes the combination less potent also. So, with a systematic approach, the findings of this study could become one weapon to fight drug resistant bacteria. However, she also adds, overcoming drug resistance will require a full arsenal.

There are several other things that need to be done – we need to tackle this problem from all sides. There needs to be a policy in place to stop the overuse of antibiotics, doctors should take necessary caution when prescribing antibiotics, overuse of antibiotics in agriculture need to be addressed and researchers must work towards developing newer antibiotics. This research can contribute it its own way by better leveraging existing drugs.

Three-drug combinations will allow doctors to prescribe lower doses of each antibiotic, which could reduce side effects. In order to ensure that the benefits of this study are far reaching, researchers plan to make available open-access software that would let other scientists and clinicians decide which combinations of antibiotics will be most effective.

References:

https://newsroom.ucla.edu/releases/three-drug-combinations-could-help-counter-antibiotic-resistance-ucla-biologists-report

https://medicalxpress.com/news/2016-07-three-drug-combinations-counter-antibiotic-resistance.html

MPS I is a rare inherited metabolic disorder caused by the deficiency of a key enzyme called alpha-L-iduronidase (IDUA). This enzyme plays a key role in breaking down complex sugars in cells and its deficiency results in abnormal accumulation of sugar debris and cell death. Presently, the only known treatments include bone marrow transplantation and intravenous enzyme replacement therapy. These treatments are only marginally effective and clinically impractical, especially when the disease enters the central nervous system. Researchers at the Perelman School of Medicine at the University of Pennsylvania are closer to finding a better way to treat children suffering from this rare disease. The findings of the study are published recently in the journal Molecular Genetics and Metabolism.

To help restore normal levels of IDUA, the researchers applied gene therapy in an ongoing preclinical trial and discovered that exposure to the human IDUA protein early in the life of an MPS I canine model increased immune tolerance to the foreign gene. Typically, dogs elicit a strong immune response to the human IDUA protein, and it makes it difficult to test if gene therapy is effective.

It was seen that the gene therapy could be tested without interference from an immune response in the dogs exposed to the human IDUA protein early in life. The researchers observed that when the gene was delivered to the brain in these dogs, there was a widespread expression of the enzyme and brain lesions that typically occur in MPS I patients were resolved.

Christian Hinderer, PhD, a senior research investigator working to complete his medical degree in the MD-PhD program at Penn remarked that their approach can test new human gene therapies in relevant animal models and may also have clinical applications for the prevention of immune responses to gene and protein replacement therapies.

The researchers worked with Plott hounds, in which MPS I naturally occurs. These dogs were originally used to develop Aldurazyme, a substance used in enzyme replacement therapy that breaks down the protein fragments left in cells.

MPS I is one of the 50 rare inherited disorders characterized by defects in the lysosomes – compartments within cells filled with enzymes to digest large molecules. When one of these enzymes is mutated, molecules that are supposed to be broken down by that enzyme accumulate within the cell and their fragments are not recycled.

MPS disorders symptoms include vision and hearing problems, hernias, and heart problems. It is estimated that in the United States 1 in 25,000 births will result in some form of MPS. The life expectancy of individuals suffering from MPS I vary, but those with the most severe form don’t live beyond 10 years.

The reason why canine models are suitable for MPS I study is because dogs have similar CNS, heart, and brain features as humans with MPS I. Also, the canine brain is closer in size to humans and better recapitulates human disease. However, the problem is that these studies can be complicated by exaggerated immune responses against the human genes. In this study, the research team demonstrated that when dogs with a genetic deficiency of IDUA were exposed to the enzyme at an early stage, they were rendered immunologically tolerant to human IDUA.

An adeno-associated viral (AAV) vector was used by researchers to introduce normal human IDUA to glial and neuronal cells of the brain and spinal cord in dogs. It was aimed to treat the CNS manifestations of MPS I at the source. The researchers observed that after a single injection of the AAV9 vector into the spinal fluid, the enzyme expression exceeded normal levels in spinal fluid, and there was a complete reversal of the characteristic brain lesions of MPS I. The researchers are hopeful that these studies will help in the planning and design of first-in-human trials.

References:

https://medicalxpress.com/news/2016-07-human-gene-therapy-rare-metabolic.html

https://www.uphs.upenn.edu/news/News_Releases/2016/07/wilson/

It is an established fact that circadian rhythm, which is our internal clock, regulates our eating and sleeping schedules. But, a new research study from the scientists at the University of Alberta reveals that our circadian rhythm has a much more important role to play than previously known. According to the new study, the results of which were published in the journal Current Biology, circadian rhythms have an important role in the normal development of an organism.

Co-author of the study Kirst King -Jones who is also an associate professor in the Department of Biological Sciences remarked that having this clock is an evolutionary advantage because it helps us to anticipate a change before it happens. Changes like temperature fluctuations, the approach of day or night, and nutrient availability can be anticipated by our biological clocks and thereby it helps in adjusting our physiological processes accordingly.

Francesca Di Cara, the study’s lead author explained that just like in insects, the circadian machinery is present in different tissues in mammals as well. To put it in layman language – there is one general master clock in the brain which controls the entire body- but, each tissue or organ also have a circadian rhythm in order to regulate different processes.

It is seen that in human patients who suffer from genetic disorders, the clock machinery is disrupted and the affected person exhibit a number of negative health consequences which includes abnormal sleep patterns, low energy levels, and impaired immune functions. It has also been noted that such disorders always affect both the central and tissue-specific clocks, which leads to one crucial question: what would happen if a single clock in a specific tissue were disrupted, leaving all other clocks intact?

In order to find an answer to this question, Di Cara and King-Jones examined fruit fly larvae whose circadian rhythms had been disrupted in a single tissue that produces steroid hormones. The effects were then compared with larvae whose rhythms had been disrupted in that single tissue as well as across the whole body.

The reason for selecting the steroid-producing tissue was that the communications between the master clock in the brain and the smaller tissue-specific clock happen through the release of hormones, including steroids and insulin. Another important about steroids is that they help in advancing the insect development through pulses that trigger the next developmental step in the insect’s life, such as the metamorphic transition from larva to pupa. The situation is similar to humans where sex steroids are involved in the onset of puberty.

The findings of their study were quite intriguing. It was found that when a specific circadian gene was disrupted across the whole body, it resulted in the fly becoming arrhythmic but was otherwise completely fine. But, when the same circadian gene was perturbed in just one tissue, it arrested the insect’s development at the larval stage. It is then unable to produce sufficient steroids to advance to the next life phase.

King -Jones remarked that the results are quite dramatic as these flies due as larvae and are unable to complete development. So, it means that when a single clock in a specific tissue stops working, it harms the body more than the situation when clocks throughout the body are damaged.

Di Cara remarked that with this study, a little bit of the interaction network in these insect steroid-producing cells has been explored. It is just the beginning of a series of studies that will define what is happening in the pituitary glands – as they are involved in the rhythmic regulation of certain steroids in humans.

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References:

https://medicalxpress.com/news/2016-08-circadian-rhythm-lot.html

https://www.ualberta.ca/science/science-news/2016/august/fruit-fly-study-shows-circadian-rhythm-does-a-lot-more-than-keep-time