Category: Antibiotics

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WHO Says New Antibiotic Treatments are Falling Behind

On By ModernMedia

The development projects of new antibiotic treatments are falling behind, despite increasing awareness of the antibiotic resistance threat, according to a recently released report by the World Health Organization. 

The WHO revealed that none of the 43 antibiotics that are currently in clinical development sufficiently address the problem of drug resistance in the world’s most dangerous bacteria.

Dr Hanan Balkhy ,Assistant Director General on AMR, WHO said that, “The persistent failure to develop, manufacture, and distribute effective new antibiotics is further fueling the impact of antimicrobial resistance (AMR) and threatens our ability to successfully treat bacterial infections.”

All of the new antibiotics released onto the market in the past few decades have been variations of those developed in the 1980s.

The impact of AMR is most severely felt in resource-constrained settings and in vulnerable populations such young children. Bacterial pneumonia and bloodstream infections are some of the major causes of childhood mortality under age 5, and about 30% of neonates with sepsis die due to bacterial infections resistant to multiple first-line antibiotics.

WHO puts out its Antibacterial Pipeline Report every year, reviewing antibiotics under development. The report evaluates the potential of the candidates to address the most threatening drug-resistant bacteria outlined in the WHO Bacterial Priority Pathogens List (WHO PPL). Since it began in 2017, this list, which includes 13 priority drug-resistant bacteria, has informed and guided priority areas for research and development.

The 2020 report paints a picture of an almost stalled pipeline with only few antibiotics in recent years receiving regulatory approval. Most of these agents in development have little extra clinical benefit over current ones, with 82% of recently approved antibiotics being derivatives of previous  ones with well-established drug-resistance, and drug resistance to these new ones is expected to emerge rapidly.

The review concludes that “overall, the clinical pipeline and recently approved antibiotics are insufficient to tackle the challenge of increasing emergence and spread of antimicrobial resistance”.

Speeding up development requires innovative approaches. For the first time. the 2020 WHO pipeline report includes a comprehensive overview of non-traditional antibacterial medicines, detailing 27 antibacterial agents in the pipeline. These range from antibodies to bacteriophages and therapies that boost the immune response and weaken bacterial effects.

The report notes that there are some promising products in different stages of development. However, only a fraction of these will ever make it to the market due to the economic and inherent scientific challenges in the drug development process. This, along with the small return on investment from successful antibiotic products, has limited the interest of major private investors and most large pharmaceutical companies.

Only a fraction of the promising products in the pipeline will make it to market because of financial and scientific obstacles in the development process. 

The preclinical and clinical pipelines continue to be driven by small- and medium-sized companies, which often struggle to finance their products through clinical trials and approval.

The COVID pandemic has deepened the global understanding of the health and economic implications of uncontrolled disease, as well as funding gaps, including investments in R&D of antimicrobial medicines and vaccines, while also demonstrating that much can be achieved with political will and sufficient funding.

“Opportunities emerging from the COVID-19 pandemic must be seized to bring to the forefront the needs for sustainable investments in R&D of new and effective antibiotics,” said Haileyesus Getahun, Director of AMR Global Coordination at WHO. “Antibiotics present the Achilles heel for universal health coverage and our global health security. We need a global sustained effort including mechanisms for pooled funding and new and additional investments to meet the magnitude of the AMR threat.”

To address funding challenges in antibiotics development, WHO partnered with the Drugs for Neglected Diseases intitive (DNDi) to set up the Global Antibiotic R&D Partnership (GARDP) to develop promising treatments.

In addition, the WHO has been working closely with other non-profit funding partners such as the CARB-X to “push” and accelerate antibacterial research. Another important new initiative is the AMR Action Fund, a partnership by the European Investment Bank. pharmaceutical companies and philanthropies.

Source: News-Medical.Net

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Prevalence of Antibiotic Resistance is Underestimated

On By ModernMedia

Antibiotic resistance to pathogenic bacteria in humans has spread farther than expected, as it has been discovered that bacteria can swap DNA far more readily than thought possible.

A growing threat, antibiotic resistance has emerged faster than thought possible. Some 33 000 deaths have occurred to antibiotic resistant infections in Europe alone, and finding new antibiotics or even alternatives are a top research priority. Totally different strains of bacteria can swap genetic information through the use of containers called plasmids. Plasmids are small containers of DNA which are kept outside of their chromosomes. When two bacteria come into contact, they can copy plasmids to one another in a process called conjugation (also known as “bacterial sex“). This is the most important means by which bacteria spread antibiotic resistance.

“In recent years, we’ve seen that resistance genes spread to human pathogens to a much greater degree than anyone expected,” said Jan Zrimec, a researcher in systems and synthetic biology at the Chalmers University of Technology. “Many of the genes appear to have originated in a wide array of bacterial species and environments, such as soil, water, and plant bacteria.

“This has been difficult to explain because although conjugation is very common, we’ve thought that there was a distinct limitation for which bacterial species can transfer plasmids to each other. Plasmids belong to different mobility groups or MOB groups, so they can’t transfer between just any bacterial species.”

Among his developments, he has written an algorithm that can sift through substantial amounts of plasmid DNA to pick out sections of DNA which are necessary for conjugation (known as oriT regions, where the enzyme relaxase can bind to and snip out DNA). This algorithm can then sort the plasmids into groups based on their oriT regions. His new method differs from the standard one because it analyses oriT regions by their physiochemical properties instead of searching DNA for the enzyme sequence for relaxase, or the point where it can bind to. This method is less time-consuming and resource intensive than the standard one.

Previously, it was thought that a plasmid had to have both the relaxase enzyme and the oriT sequence to bind to, but a bacterial cell can have an oriT region for conjugation to occur. With his new algorithm, he has been able to explore the DNA of 4600 plasmids from different bacteria found in nature.
– There may be eight times as many oriT regions than those discovered with standard methods.
– There may be twice as many mobile plasmids as previously known.
– There also may be twice as many bacterial species with mobile plasmids as previously known.
– More than half the plasmids have an oriT group matching to an enzyme for conjugation from a plasmid that already been classified in a different MOB group. This means that they could be transferred from a different plasmid in the same cell.

The last finding suggests that there may be far greater interchange between bacteria than had been previously been believed.

“This has been a major limitation of the research field up to now,” Zrimec said. “I hope that the methods will be able to benefit large parts of the research into antibiotic resistance, which is an extremely interdisciplinary and fragmented area. The methods can be used for studies aiming to develop more effective limitations to antibiotic use, instructions for how antibiotics are to be used, and new types of substances that can prevent the spread of resistance genes at the molecular level.”

Source: News-Medical.Net

Journal information: Zrimec, J. (2021) Multiple plasmid origin‐of‐transfer regions might aid the spread of antimicrobial resistance to human pathogens. MicrobiologyOpen.doi.org/10.1002/mbo3.1129.

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Single Water Molecule Is the Key to Macrolide Resistance

On By ModernMedia

High resolution molecular structures produced by researchers at the University of Illinois Chicago show that the effectiveness of the macrolides class of antibiotics – and bacterial resistance to it – depends on interaction with a single water molecule. 

Macrolides have a broad spectrum of use against most gram-positive bacteria and are a widely used treatment  for a variety of infections. Clarithromycin, for example, is used as a mainstay treatment for respiratory infections. Due to antibiotic overuse, antibiotic resistance has emerged Macrolides interrupt protein biosynthesis in the ribosomes of pathogenic bacteria, and are one of the most successful classes of antibiotics to use this mechanism of action. The macrolides accomplish this by entering the cell and binding to the bacteria’s ribosomes, preventing them from manufacturing and releasing new proteins. As a result of the halt in protein synthesis, the bacteria can no longer grow or replicate. However, mutations came about that rendered the bacteria resistant.

Seeking to understand how the bacteria came about their resistance, the researchers learned how to capture images of the ribosome and the macrolide invading it. The researchers discovered that precisely one water molecule was required for the antibiotic to bind to the ribosome.

Corresponding author Yury Polikanov, associate professor of biological sciences at UIC, said: “We compared the hi-res structures of the ribosomes from sensitive and resistant bacteria and noticed that a water molecule that is needed for the tight antibiotic binding was not present in the ribosomes from the drug-resistant bugs. In the ribosomes from the drug-resistant bacteria, there was simply no room for this water molecule.”

The mutation that conferred macrolide resistance adds a pair of methyl groups to where the macrolide molecule normally binds to the ribosome, and the water molecule instead disrupts the binding.  

“We are very much excited by this discovery,” Polikanov said. “Because we now know how exactly macrolide antibiotics interact with their target, the ribosome. This discovery is important because it will inform and facilitate the development of new antibiotics that do not need this water molecule for binding. There is a huge demand for such drugs that are able to kill even those bacteria that became resistant to the currently used drugs.”

Source: News-Medical.Net

Journal information: Svetlov, M.S., Syroegin, E.A., Aleksandrova, E.V. et al. Structure of Erm-modified 70S ribosome reveals the mechanism of macrolide resistance. Nat Chem Biol (2021). https://doi.org/10.1038/s41589-020-00715-0

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A Common Antibiotic Shows Promise for Zika Protection

On By ModernMedia

A huge search through known drug compounds showed that a common antibiotic has been shown to be effective against Zika in vitro. Zika, which causes foetal microcephaly, preferentially attacks brain stem cells. 

In order to find a compound that confers Zika protection, the researchers searched for drugs that prevent virus reproduction by blocking the activity of a protein called NS2B-NS3 Zika virus protease. This protease acts to assemble the components of new Zika viruses from protein produced by the virus’ RNA injection into a cell.

“Proteases act like scissors. Blocking protease activity is an effective strategy for counteracting many viruses,” said study leader Rachel Abrams, PhD. “We wanted to look as far and wide as possible for drugs that could prevent the protease from snipping the Zika virus polyprotein into its active pieces.”

To find out which compounds blocked the protease, hundreds of assays were conducted against three different libraries.

An initial screen of 2 000 compounds showed that common tetracycline-based antibiotic drugs, such as methacycline were able to block the protease.

A larger screen of 10 000 compounds found potential candidates in an investigational anti-inflammatory medicine, MK-591, and a failed anti-Alzheimer’s disease drug, JNJ-404.  

Finally, 130 000 compounds were screened virtually, with machine learning being used to investigate what made a good candidate.

The candidate compounds were shown to reduce Zika infections of brain stem cells in vitro.

As methacycline is known to cross the placental barrier, this emerged as a promising candidate to treat pregnant women infected with the virus. However in mouse models, treatment with methacycline only partially protected the brains of newborn mice.

“These results suggest that tetracycline-based antibiotics may at least be effective at preventing the neurological problems associated with Zika virus infections,” said Dr Abrams. “Given that they are widely used, we hope that we can rapidly test their potential in clinical trials.”

Source: News-Medical.Net