Breaking News
December 16, 2018 - ‘Easy Way Out’? Stigma May Keep Many From Weight Loss Surgery
December 16, 2018 - Gout drug may protect against chronic kidney disease
December 16, 2018 - Talking about memories enhances the wellbeing of older and younger people
December 16, 2018 - Occupational exposure to pesticides increases risk for cardiovascular disease among Latinos
December 16, 2018 - A biomarker in the brain’s circulation system may be Alzheimer’s earliest warning
December 16, 2018 - Magnesium may play important role in optimizing vitamin D levels, study shows
December 16, 2018 - The effect of probiotics on intestinal flora of premature babies
December 16, 2018 - Parents spend more time talking with kids about mechanics of using mobile devices
December 16, 2018 - Biohaven Announces Positive Results from Ongoing Rimegepant Long-Term Safety Study
December 16, 2018 - Arterial stiffness may predict dementia risk
December 16, 2018 - Study explores link between work stress and increased cancer risk
December 16, 2018 - Sex work criminalization linked to incidences of violence finds study
December 16, 2018 - Johns Hopkins researchers discover swarming behavior in fish-dwelling parasite
December 16, 2018 - Schistosomiasis prevention and treatment could help control HIV
December 16, 2018 - Early postpartum opioids linked with persistent usage
December 16, 2018 - Johns Hopkins researchers identify molecular causes of necrotizing enterocolitis in preemies
December 16, 2018 - Advanced illumination expands capabilities of light-sheet microscopy
December 16, 2018 - Alzheimer’s could possibly be spread via contaminated neurosurgery
December 16, 2018 - Unraveling the complexity of cancer biology can prompt new avenues for drug development
December 16, 2018 - Inflammatory Bowel Disease, Prostate Cancer Linked
December 16, 2018 - Cannabis youth prevention strategy should target mental wellbeing
December 15, 2018 - Recent developments and challenges in hMAT inhibitors
December 15, 2018 - Sewage bacteria found lurking in Hudson River sediments
December 15, 2018 - CDC selects UMass Amherst biostatistician model that helps predict influenza outbreaks
December 15, 2018 - Researchers reveal brain mechanism that drives itch-evoked scratching behavior
December 15, 2018 - New computer model helps predict course of the disease in prostate cancer patients
December 15, 2018 - Obesity to Blame for Almost 1 in 25 Cancers Worldwide
December 15, 2018 - How the brain tells you to scratch that itch
December 15, 2018 - New findings could help develop new immunotherapies against cancer
December 15, 2018 - World’s largest AI-powered medical research network launched by OWKIN
December 15, 2018 - Young people suffering chronic pain battle isolation and stigma as they struggle to forge their identities
December 15, 2018 - Lifespan extension at low temperatures depends on individual’s genes, study shows
December 15, 2018 - New ingestible capsule can be controlled using Bluetooth wireless technology
December 15, 2018 - Researchers uncover microRNAs involved in the control of social behavior
December 15, 2018 - Research offers hope for patients with serious bone marrow cancer
December 15, 2018 - Link between poverty and obesity is only about 30 years old, study shows
December 15, 2018 - Mass spectrometry throws light on old case of intentional heavy metal poisoning
December 15, 2018 - BeyondSpring Announces Phase 3 Study 105 of its Lead Asset Plinabulin for Chemotherapy-Induced Neutropenia Meets Primary Endpoint at Interim Analysis
December 15, 2018 - Study finds that in treating obesity, one size does not fit all
December 15, 2018 - Tenacity and flexibility help maintain psychological well-being, mobility in older people
December 15, 2018 - Study reveals role of brain mechanism in memory recall
December 15, 2018 - High levels of oxygen encourage the brain to remain in deep, restorative sleep
December 15, 2018 - Experimental HIV vaccine strategy works in non-human primates, research shows
December 15, 2018 - Genetically modified pigs could limit replication of classical swine fever virus, study shows
December 15, 2018 - FDA Approves Herzuma (trastuzumab-pkrb), a Biosimilar to Herceptin
December 15, 2018 - Cost and weight-loss potential matter most to bariatric surgery patients
December 15, 2018 - Cancer Research UK and AstraZeneca open new Functional Genomics Centre
December 15, 2018 - New research lays out potential path for treatment of Huntington’s disease
December 15, 2018 - Prestigious R&D 100 Award presented to Leica Microsystems
December 15, 2018 - Study shows septin proteins detect and kill gut pathogen, Shigella
December 15, 2018 - Study sheds new light on disease-spreading mosquitoes
December 15, 2018 - 2017 Saw Slowing in National Health Care Spending
December 15, 2018 - Monitoring movement reflects efficacy of mandibular splint
December 15, 2018 - Study supports BMI as useful tool for assessing obesity and health
December 15, 2018 - Self-guided, internet-based therapy platforms effectively reduce depression
December 15, 2018 - Organically farmed food has bigger climate impact than conventional food production
December 15, 2018 - Faster, cheaper test has potential to enhance prostate cancer evaluation
December 15, 2018 - Researchers study abnormal blood glucose levels of patients after hospital discharge
December 15, 2018 - Swedish scientists explore direct association of dementia and ischemic stroke deaths
December 15, 2018 - Study finds 117% increase in number of dementia sufferers in 26 years
December 15, 2018 - Eczema Can Drive People to Thoughts of Suicide: Study
December 15, 2018 - Link between neonatal vitamin D deficiency and schizophrenia confirmed
December 15, 2018 - Nurse denied life insurance because she carries naloxone
December 15, 2018 - Ritalin drug affects organization of pathways that build brain networks used in attention, learning
December 15, 2018 - Research pinpoints two proteins involved in creation of stem cells
December 15, 2018 - Gut bacteria may modify effectiveness of anti-diabetes drugs
December 15, 2018 - A new type of ‘painless’ adhesive for biomedical applications
December 15, 2018 - Early physical therapy associated with reduction in opioid use
December 15, 2018 - Breast cancer protection from pregnancy begins many decades later, study finds
December 15, 2018 - How often pregnant women follow food avoidance strategy to prevent allergy in offspring?
December 15, 2018 - Using machine learning to predict risk of developing life-threatening infections
December 15, 2018 - How imaginary friends could boost children’s development
December 15, 2018 - Folate deficiency creates more damaging chromosomal abnormalities than previously known
December 15, 2018 - Study provides new insights into molecular mechanisms underlying role of amyloid in Alzheimer’s disease
December 15, 2018 - For the asking, a check is in the mail to help pay for costly drugs
December 15, 2018 - UA scientists uncover biological processes leading to rare brain disorder in babies
December 15, 2018 - The largest database on industrial poisons
December 15, 2018 - ESMO Immuno-Oncology Congress showcases novel technologies set to benefit many cancer patients
December 15, 2018 - Ovid Therapeutics Announces Plans to Move into a Phase 3 Trial in Pediatric Patients Based on End-of-Phase 2 Meeting for OV101 in Angelman Syndrome
December 15, 2018 - Left ventricular noncompaction – Genetics Home Reference
New naturally occurring antibiotic found effective against Mycobacterium tuberculosis

New naturally occurring antibiotic found effective against Mycobacterium tuberculosis

image_pdfDownload PDFimage_print

A naturally occurring antibiotic called kanglemycin A is effective against Mycobacterium tuberculosis, the bacteria that cause tuberculosis, even in drug-resistant strains, according to an international team of researchers who used chemistry, molecular biology, microbiology, and X-ray crystallography to show how the compound maintains its activity. A paper describing the research appears September 20, 2018 in the journal Molecular Cell.

The compound, kanglemycin A, is related to the antibiotic rifampicin, according to Katsuhiko Murakami, professor of biochemistry and molecular biology at Penn State and one of leaders of the project. “Rifampicin is already part of the cocktail of antibiotics used to treat tuberculosis, but many strains of the tuberculosis-causing bacteria have developed resistance to it,” Murakami said.

“Tuberculosis is the leading cause of death by infectious disease worldwide,” said Murakami. “Development of rifampicin resistance in M. tuberculosis has made treatment of this disease very difficult since it extends treatment time of tuberculosis from 6 months to 2 years. Identifying new compounds that are effective against the rifampicin-resistant bacteria is incredibly important for public health.”

The researchers screened a library of naturally occurring compounds from U.K. biotech company Demuris Ltd. for their ability to inhibit bacterial cell growth or prevent the production of RNA–an essential process in all living organisms–in bacteria. They discovered that a compound named kanglemycin A was effective at inhibiting RNA production even in rifampicin-resistant bacteria.

“Kanglemycin A is related to rifampicin, an antibiotic that functions by binding to bacterial RNA polymerase, the enzyme responsible for RNA production, and preventing it from making more RNA,” said Murakami. “Understanding how kanglemycin A manages to maintain its affinity to rifampicin-resistant RNA polymerase and stay active against the drug-resistant bacteria will help to accelerate its approval for use in patients with tuberculosis.”

To determine the mechanism of kanglemycin A action against rifampicin-resistant RNA polymerase, the Murakami group used X-ray crystallography to determine the three-dimensional structure of the complex of kanglemycin A bound to bacterial RNA polymerase. It was known that rifampicin binds to a groove in the RNA polymerase molecule and that mutations that change the amino-acid sequence of the RNA polymerase can prevent this binding, while maintaining the ability to produce RNA. Kanglemycin A binds to the same groove, but its structure revealed extensions that also bind just outside the groove allowing it to inhibit activity of rifampicin-resistant RNA polymerase.

“The X-ray structure actually revealed that kanglemycin A has two modifications that improve its function compared to rifampicin,” said Murakami. “First, one of modifications allows it to bind just outside of the rifampicin binding pocket increasing the strength of its affinity to the RNA polymerase in rifampicin-resistant bacteria. Second, another modification actually allows kanglemycin A to stop the synthesis of RNA even earlier than rifampicin.”

“It is a really exciting finding,” said Nikolay Zenkin, professor of molecular biology at Newcastle University in the U.K. and one of leaders of the project. “The previously unknown interactions of the unique chemical groups of kanglemycin A with RNA polymerase will direct the development of antibiotics against rifampicin-resistant M. tuberculosis. Approximately one third of the world’s population is already infected with M. tuberculosis, and 600,000 people every year are diagnosed with rifampicin-resistant tuberculosis. Our work is the first step in developing a new drug for the treatment of these patients.”

The research was led by Zenkin and Murakami, working closely with Newcastle University spin out company, Demuris Ltd, which will be taking on the commercialization of the new compounds. In addition, the research team included Vadim Molodtsov and Yeonoh Shin at Penn State; Hamed Mosaei, Bernhard Kepplinger, John Harbottle, Lucia Ceccaroni, Stephanie Morton-Laing, Corinne Wills, William Clegg, Yulia Yuzenkova, and Michael John Hall at Newcastle University in the United Kingdom; Christopher William Moon, Rose Elizabeth Jeeves, and Joanna Bacon in the TB Research Group of the U.K. National Infection Service; Emma Claire Louise Marrs and John David Perry at Freeman Hospital in Newcastle upon Tyne, U.K.; and Nicholas Allenby and Jeff Errington at Demuris Limited, Newcastle upon Tyne, U.K.

Source:

http://science.psu.edu/news-and-events/2018-news/Murakami9-2018

Tagged with:

About author

Related Articles