PRESS-NEWS.org - Press Release Distribution
PRESS RELEASES DISTRIBUTION

CHOP researchers establish novel approach for developing new antibiotics

New study proposes structure-guided design to create prodrugs that act as a "Trojan Horse," allowing antibiotics to reach resistant bacteria

CHOP researchers establish novel approach for developing new antibiotics
2021-07-19
(Press-News.org) Philadelphia, July 19, 2021--Researchers at Children's Hospital of Philadelphia (CHOP) have developed a novel method for producing new antibiotics to combat resistant bacteria. Through an approach that would target bacteria with an antibiotic that is masked by a prodrug, which the bacteria would themselves remove, the researchers identified a method that would allow for development of new, effective antibiotics that could overcome issues of resistance. The findings were published today in eLife.

"We've created a sort of 'Trojan Horse' that would allow antibiotics to reach desired tissues undisturbed, until the bacteria itself activates the drug, effectively releasing an 'army' of antibiotics," said senior author Audrey R. Odom John, MD, PhD, Chief of the Division of Pediatric Infectious Diseases at CHOP. "Using structure-guided design, we have developed a new way to design better antibiotics. Given the growing concern over antimicrobial resistance, we think this is an important step forward."

Antimicrobial resistance poses a serious threat to public health, with some estimates suggesting that antimicrobial-resistant infections will cause as many as 10 million deaths per year by 2050. To combat this public health threat, scientists will need to develop new, chemically distinct antibiotics that can circumvent antimicrobial resistance, but most attempts to do so have either failed in animal or human models or have been unable to get sufficient levels of treatment to the desired tissues.

To tackle this problem, the researchers took a new approach that relied on exploiting bacterial metabolism, processes that are essential for bacteria to thrive. Drugs that inhibit these processes could eradicate the bacteria, but the chemical group that would inhibit those enzymes has a negative charge, which prevents the drugs from entering cells, creating a challenge.

One way to overcome that challenge is to chemically mask the undesirable negative charge with another chemical group. This strategy, known as prodrugging, adds a sort of shield - the "Trojan Horse" - that masks the negative charge, allows the drug to enter the cell, and then is removed during absorption to allow the original antibiotic to be taken up. However, the prodrug must also be resistant to host enzymes; otherwise, the prodrug mask will be removed too early, and the drug will never reach the desired tissue.

Focusing on Staphylococcus aureus, since methicillin-resistant S. aureus (MRSA) has been labeled a "serious threat" by the Centers for Disease Control and Prevention, the researchers looked for bacterial enzymes that interacted with specific targets that would not interact with host enzymes. Doing so, they were able to characterize two enzymes - GloB and FrmB - that each have defined substrate specificities - that is, highly specific molecules with which they will interact - and, importantly, those specificities are different than those of human enzymes. Thus, these enzymes could remove prodrug additions, activating the antibiotic, without the prodrugs first being degraded by the host.

Having determined GloB and FrmB were suitable bacterial enzyme targets, the researchers characterized the three-dimensional structures of GloB and FrmB, which confirmed their active sites and will enable ongoing structure-guided design of FrmB- and GloB-targeted prodrugs.

"This work paves the way for structure-guided development of S. aureus-specific prodrugs and establishes a pipeline for the identification of additional microbial prodrug activating enzymes," John said. "We anticipate that these approaches will both guide the development of novel antimicrobials and lead to a more robust arsenal of anti-infective compounds with targeted specificity for the microbe over the human host."

INFORMATION:

Miller et al. "Structure-guided microbial targeting of antistaphylococcal prodrugs," eLife, online July 19, 2021, DOI: 10.7554/eLife.66657

About Children's Hospital of Philadelphia: Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 595-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu


[Attachments] See images for this press release:
CHOP researchers establish novel approach for developing new antibiotics

ELSE PRESS RELEASES FROM THIS DATE:

Firefighters found to have persistent lung damage from Fort McMurray wildfire

Firefighters found to have persistent lung damage from Fort McMurray wildfire
2021-07-19
(Edmonton, AB) Firefighters at the centre of the battle against the massive Fort McMurray wildfire in 2016 have persistent lung damage, according to new findings published by a University of Alberta occupational health research team. "Those who were dealing with burning organic matter were exposed to a barrage of small particles in the smoke, and the ones with the highest exposure have long-term consequences," said principal investigator Nicola Cherry, an occupational epidemiologist, professor of medicine and Tripartite Chair of Occupational Health in the Faculty of Medicine & Dentistry. The firefighters had more ...

A small molecule induces readthrough of cystic fibrosis CFTR nonsense mutations

A small molecule induces readthrough of cystic fibrosis CFTR nonsense mutations
2021-07-19
BIRMINGHAM, Ala. - An experimental drug reported in Nature Communications suggests that a "path is clearly achievable" to treat currently untreatable cases of cystic fibrosis disease caused by nonsense mutations. This includes about 11 percent of cystic fibrosis patients, as well as patients with other genetic diseases, including Duchenne muscular dystrophy, β-thalassemia and numerous types of cancers, that are also caused by nonsense mutations. The drug is a small molecule with a novel mechanism of action, say David Bedwell, Ph.D., and Steven Rowe, M.D., MSPH, co-senior authors. Bedwell is professor and chair of the University of Alabama at Birmingham Department of Biochemistry and Molecular ...

New sunspot catalogue to improve space weather predictions

New sunspot catalogue to improve space weather predictions
2021-07-19
Scientists from the University of Graz, Kanzelhöhe Observatory, Skoltech, and the World Data Center SILSO at the Royal Observatory of Belgium, have presented the Catalogue of Hemispheric Sunspot Numbers. It will enable more accurate predictions of the solar cycle and space weather, which can affect human-made infrastructure both on Earth and in orbit. The study came out in the Astronomy & Astrophysics journal, and the catalogue is available from SILSO -- the World Data Center for the production, preservation, and dissemination of the international sunspot number. Our Sun is a big boiling ball of gas, most of which is so hot that electrons are ripped off from atoms, creating a circulating mix of charged particles, called plasma. These moving charges ...

Repairing hearts with deadly spider venom

Repairing hearts with deadly spider venom
2021-07-19
A potentially life-saving treatment for heart attack victims has been discovered from a very unlikely source - the venom of one of the world's deadliest spiders. A drug candidate developed from a molecule found in the venom of the Fraser Island (K'gari) funnel web spider can prevent damage caused by a heart attack and extend the life of donor hearts used for organ transplants. The discovery was made by a team led by END ...

Researchers reveal pathogenesis and therapeutic strategy of pre-engraftment syndrome

Researchers reveal pathogenesis and therapeutic strategy of pre-engraftment syndrome
2021-07-19
The research team led by Prof. WEI Haiming and Prof. TIAN Zhigang from Division of Life Sciences and Medicine, University of Science and Technology of China (USTC) of the Chinese Academy of Sciences (CAS), collaborating with the research group led by Prof. SUN Zimin from the First Affiliated Hospital of USTC revealed the pathological mechanism of severe pre-engraftment syndrome (PES) after umbilical cord blood transplantation, not only providing a treatment strategy for patients with PES, but significantly guiding for further improvement in the curative effect of unrelated cord blood transplantation (UCBT). This study was published in Nature Communications. UCBT is an important means to cure hematological ...

Deconstructing the infectious machinery of SARS-CoV-2

Deconstructing the infectious machinery of SARS-CoV-2
2021-07-19
In February 2020, a trio of bio-imaging experts were sitting amiably around a dinner table at a scientific conference in Washington, D.C., when the conversation shifted to what was then a worrying viral epidemic in China. Without foreseeing the global disaster to come, they wondered aloud how they might contribute. Nearly a year and a half later, those three scientists and their many collaborators across three national laboratories have published a comprehensive study in Biophysical Journal that - alongside other recent, complementary studies of coronavirus proteins ...

Chemists found an effective remedy for "aged" brain diseases

Chemists found an effective remedy for aged brain diseases
2021-07-19
Russian scientists have synthesized chemical compounds that can stop the degeneration of neurons in Alzheimer's, Parkinson's, and other severe brain pathologies. These substances can provide a breakthrough in the treatment of neurodegenerative pathologies. New molecules of pyrrolyl- and indolylazine classes activate intracellular mechanisms to combat one of the main causes of "aged" brain diseases - an excess of so-called amyloid structures that accumulate in the human brain with age. The essence of the study was published in the European Journal of Medicinal Chemistry. Experts from the Institute of Cytology of the Russian Academy of Sciences, the Institute of Organic Synthesis of the Ural Branch of the Russian ...

The mathematics of repulsion for new graphene catalysts

The mathematics of repulsion for new graphene catalysts
2021-07-19
A new mathematical model helps predict the tiny changes in carbon-based materials that could yield interesting properties. Scientists at Tohoku University and colleagues in Japan have developed a mathematical model that abstracts the key effects of changes to the geometries of carbon material and predicts its unique properties. The details were published in the journal Carbon. Scientists generally use mathematical models to predict the properties that might emerge when a material is changed in certain ways. Changing the geometry of three-dimensional (3D) graphene, which is made of networks of carbon atoms, by adding chemicals or introducing topological defects, can improve its catalytic properties, for example. But it has been difficult for scientists to understand why this happens exactly. The ...

Understanding the physics in new metals

Understanding the physics in new metals
2021-07-19
Researchers from the Paul Scherrer Institute PSI and the Brookhaven National Laboratory (BNL), working in an international team, have developed a new method for complex X-ray studies that will aid in better understanding so-called correlated metals. These materials could prove useful for practical applications in areas such as superconductivity, data processing, and quantum computers. Today the researchers present their work in the journal Physical Review X. In substances such as silicon or aluminium, the mutual repulsion of electrons hardly affects the material properties. Not so with so-called correlated materials, in which the electrons interact strongly with one another. The movement of one electron in a correlated material leads ...

The era of single-spin color centers in silicon carbide is approaching

2021-07-19
Prof. LI Chuanfeng, Prof. XU Jinshi and their colleagues from Prof. GUO Guangcan's group, University of Science and Technology of China (USTC) of the Chinese Academy of Sciences (CAS), realized the high-contrast readout and coherent manipulation of a single silicon carbide divacancy color center electron spin at room temperature for the first time in the world, in cooperation with Prof. Adam Gali, from the Wigner Research Centre for Physics in Hungary. This work was published in National Science Review on July 5, 2021. Solid-state spin color centers are of utmost importance in many applications of quantum technologies, the outstanding one among which is the nitrogen-vacancy (NV) center in diamond. Since the detection ...

LAST 30 PRESS RELEASES:

Andrew E. Place, MD, PhD appointed as Dana-Farber/Boston Children’s Cancer and Blood Disorders Center Vice President, Pediatric Chief Medical Officer

COVID-19 antibody discovery could explain long COVID

Wild plants face viral surprise

Storing electrons from hydrogen for clean chemical reactions

Unlocking how to use mRNA to target Alzheimer’s disease

Kessler Foundation secures $770,000 in grants to advance leading-edge spinal cord research

Going ‘back to the future’ to forecast the fate of a dead Florida coral reef

How extratropical ocean-atmosphere interactions can contribute to the variability of jet streams in the Northern Hemisphere

MSK Research Highlights, March 28, 2024

USDA, Nueta Hidatsa Sahnish College collaborate to support Indigenous Seed Sovereignty

For younger women, mental health now may predict heart health later

Missed opportunity: AEDs near cardiac arrests rarely used by bystanders

Eggs may not be bad for your heart after all

Alcohol raises heart disease risk, particularly among women

TTUHSC announces new center for nursing research

Adding just enough fuel to the fire

Impact of synbiotic supplements on the gut microbiome and overall health of penguins

Promising advances in organosilica membranes for separating organic liquid mixtures

Cell phone video technology unveils new method for analyzing walking and gait

Ancient isolation’s impact on modern ecology

Synaptic protein change during development offers clues on evolution and disease

How commercial rooftop solar power could bring affordable clean energy to low-income homes

Taking a closer look at pulmonary fibrosis genetics

Cats with MDR1 mutation at risk of severe reactions to popular medication

IOP Publishing and IPEM mandate reporting of sex and gender in research 

Dogs trained to detect trauma stress by smelling humans’ breath

Electronic device thermal management made simpler and slightly better!

Study: Dangerous surgical site infections can be reduced with simple prevention protocol

Genetic testing of patients with atrial fibrillation can alert clinicians to potential development of life-threatening conditions

Artificial Intelligence tool successfully predicts fatal heart rhythm

[Press-News.org] CHOP researchers establish novel approach for developing new antibiotics
New study proposes structure-guided design to create prodrugs that act as a "Trojan Horse," allowing antibiotics to reach resistant bacteria