Category: Antibiotics

Categories : Antibiotics Medical Research & TechnologyTags :

Human Breast Milk Could Yield Antibiotic Secrets

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Researchers believe that antibacterial properties of sugars in human breast milk could be harnessed for new antimicrobial therapies.

Group B Streptococcus (GBS) bacteria are a common cause of blood infections, meningitis and stillbirth in newborns, and are becoming resistant to antibiotics. Researchers have now discovered that human milk oligosaccharides (HMOs), short strings of sugar molecules abundant in breast milk, can help prevent GBS infections in human cells and tissues and in mice. This might yield new antibiotic treatments, the researchers believe. 

“Our lab has previously shown that mixtures of HMOs isolated from the milk of several different donor mothers have antimicrobial and antibiofilm activity against GBS,” says Rebecca Moore, who is presenting the work at a meeting of the American Chemical Society (ACS). “We wanted to jump from these in vitro studies to see whether HMOs could prevent infections in cells and tissues from a pregnant woman, and in pregnant mice.” Moore is a graduate student in the labs of Steven Townsend, PhD, at Vanderbilt University and Jennifer Gaddy, PhD, at Vanderbilt University Medical Center.

According to the US Centers for Disease Control and Prevention, about 2000 babies in the U.S. get GBS each year, with 4-6% of them dying from it. The bacteria are often transferred from mother to baby during labour and delivery. An expectant mother who tests positive for GBS is usually given intravenous antibiotics during labor to help prevent early-onset infections, which occur during the first week of life. Notably, late-onset infections (which happen from one week to three months after birth) are more common in formula-fed than breastfed infants, suggesting breast milk has factors which could help protect against GBS. If so, the sugars could be a replacement for current antibiotics which are steadily becoming less effective.

The researchers studied the effects of combined HMOs from several mothers on GBS infection of placental macrophages and of the gestational membrane. “We found that HMOs were able to completely inhibit bacterial growth in both the macrophages and the membranes, so we very quickly turned to looking at a mouse model,” Moore says. They examined whether HMOs could prevent a GBS infection from spreading through the reproductive tract of pregnant mice. “In five different parts of the reproductive tract, we saw significantly decreased GBS infection with HMO treatment,” Moore notes.

To determine which HMOs and other oligosaccharides have these antimicrobial effects and why, the researchers made an artificial two-species microbiome with GBS and the beneficial Streptococcus salivarius species growing in a tissue culture plate, separated by a semi-permeable membrane. Then, the researchers added oligosaccharides that are commonly added to infant formula, called galacto-oligosaccharides (GOS), which are derived from plants. In the absence of the sugar, GBS suppressed the growth of the “good” bacteria, but GOS helped this beneficial species grow. “We concluded that GBS is producing lactic acid that inhibits growth, and then when we add the oligosaccharide, the beneficial species can use it as a food source to overcome this suppression,” Moore explained.
The first HMOs tested did not have this effect, but Townsend says it’s likely that one or more of the over 200 unique sugars in human milk will show activity in the artificial microbiome assay. There are likely two reasons why HMOs can treat and prevent GBS infection: they prevent pathogens from sticking to tissue surfaces and forming a biofilm, and they could also act as a prebiotic by promoting good bacteria growth.

“HMOs have been around as long as humans have, and bacteria have not figured them out. Presumably, that’s because there are so many in milk, and they’re constantly changing during a baby’s development,” Townsend said. “But if we could learn more about how they work, it’s possible that we could treat different types of infections with mixtures of HMOs, and maybe one day this could be a substitute for antibiotics in adults, as well as babies.”

Source: American Chemical Society

Categories : Antibiotics COVIDTags :

Bacterial Superinfections in COVID Rarer Than Expected

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Only 21 percent of patients with severe pneumonia caused by SARS-CoV-2 have a documented bacterial superinfection at the time of intubation, resulting in potential overuse of antibiotics, according to new research.

Superinfection occurs when another, usually different, infection is superimposed on the initial infection. In this case, it is bacterial pneumonia during severe viral pneumonia.

Dr Wunderink and co-authors reported their findings in a study published online in the Journal of Respiratory and Critical Care Medicine, which shows that the usual clinical criteria used to diagnose bacterial pneumonia could not distinguish between those with bacterial superinfection and those with severe SARS-CoV-2 infection only.

According to the authors, there is weak evidence behind current guidelines recommending that patients with SARS-CoV-2 pneumonia receive empirical antibiotics on hospital admission for suspected bacterial superinfection. In other published clinical trials of patients with SARS-CoV-2 pneumonia, rates of superinfection pneumonia are unexpectedly low.
“More accurate assessment other than just reviewing clinical parameters is needed to enable clinicians to avoid using antibiotics in the majority of these patients, but appropriately use antibiotics in the 20-25 percent who have a bacterial infection as well,” said Dr Wunderink.

The team conducted an observational study to determine the prevalence and cause of bacterial superinfection at the time of initial intubation and the incidence and cause of subsequent bacterial ventilator-associated pneumonia (VAP) in 179 patients with severe SARS-CoV-2 pneumonia which required mechanical ventilation.

The researchers analysed 386 bronchoscopic bronchoalveolar lavage fluid samples from patients, and actual antibiotic use was compared with guideline-recommended therapy. Bacterial superinfection within 48 hours of intubation was detected in 21 percent of patients; 72 patients (44.4 percent) developed at least one VAP episode; and 15 (20.8 percent) of initial VAPs were caused by difficult-to-treat bacteria.

The authors found that in patients with severe SARS-CoV-2 pneumonia, bacterial superinfection at the time of intubation occurred in less than 25 percent of patients. Guideline-based empirical antibiotic management at the time of intubation would have resulted in antibiotic overuse.

The researchers believe that their findings have multiple implications for antibiotic guidelines: “Rapid diagnostic tests are important for helping identify suspected pneumonia in intubated patients. This can have major clinical implications because the current approach of using clinically defined risk factors for suspected methicillin-resistant staphylococcus aureus (MRSA) or pseudomonas bacteria as the cause of pneumonia still grossly overestimate the true incidence of these pathogens. In addition, the recommendation for empirical antibiotic treatment of worsening viral community-acquired pneumonia (now requiring intubation) may need to be revisited. This is not only true for SARS-CoV-2 but potentially for severe influenza as well.”

“An accurate diagnosis of suspected pneumonia allows clinicians to safely avoid or use narrow spectrum antibiotics for many patients,” Dr Wunderink added.  “While multiple interventions impact mortality in these critically ill patients, the low mortality in our study with more limited antibiotic treatment suggests that our approach was safe.”

Source: American Thoracic Society

Categories : Antibiotics CancerTags :

Old Antibiotics as New Weapons against Melanoma

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Researchers may have hit upon a new weapon in the fight against melanoma: antibiotics that target a vulnerability in the ‘power plants’ of cancer cells when they try to survive cancer therapy.

“As the cancer evolves, some melanoma cells may escape the treatment and stop proliferating to ‘hide’ from the immune system. These are the cells that have the potential to form a new tumor mass at a later stage,” explains cancer researcher and RNA biologist Eleonora Leucci at KU Leuven, Belgium. “In order to survive the cancer treatment however, those inactive cells need to keep their ‘power plants’—the mitochondria—switched on at all times.” As mitochondria derive from bacteria that, over time, started living inside cells, they are very vulnerable to a specific class of antibiotics. This is what gave us the idea to use these antibiotics as anti-melanoma agents.”

The researchers implanted patient-derived tumors into mice, which were then treated with antibiotics, either as alone or in combined with existing anti-melanoma therapies. Leucci observed: “The antibiotics quickly killed many cancer cells and could thus be used to buy the precious time needed for immunotherapy to kick in. In tumors that were no longer responding to targeted therapies, the antibiotics extended the lifespan of—and in some cases even cured—the mice.”

The researchers made use of nearly antibiotics rendered nearly obsolete because of antibiotic resistance. However, this does not affect the efficacy of the treatment in this study, Leucci explained. “The cancer cells show high sensitivity to these antibiotics, so we can now look to repurpose them to treat cancer instead of bacterial infections.”

However, patients with melanoma should not try to experiment, warned Leucci. “Our findings are based on research in mice, so we don’t know how effective this treatment is in human beings. Our study mentions only one human case where a melanoma patient received antibiotics to treat a bacterial infection, and this re-sensitized a resistant melanoma lesion to standard therapy. This result is cause for optimism, but we need more research and clinical studies to examine the use of antibiotics to treat cancer patients. Together with oncologist Oliver Bechter (KU Leuven/UZ Leuven), who is a co-author of this study, we are currently exploring our options.”

Source: KU Leuven

Journal information: Roberto Vendramin et al, Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma, Journal of Experimental Medicine (2021). DOI: 10.1084/jem.20210571

Categories : Antibiotics Diseases, Syndromes and ConditionsTags :

Untreated Sewage is a Driver of Antibiotic Resistance

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Photo by Jordan Opel on Unsplash
Photo by Jordan Opel on Unsplash

Contamination of urban lakes, rivers and surface water by human waste is creating pools of ‘superbugs’ in Low- and Middle-Income Countries (LMIC), according to new research. However, improving access to clean water, sanitation and sewerage infrastructure could help to improve public health.

For the study, researchers studied bodies of water in urban and rural sites in three areas of Bangladesh: Mymensingh, Shariatpur and Dhaka. In comparison to rural settings, they detected more antibiotic resistant faecal coliforms in urban surface water , consistent with reports of such bacteria in rivers across Asia. Their findings were published in mSystems.

Lead author Willem van Schaik, Professor of Microbiology and Infection at the University of Birmingham, commented: “The rivers and lakes of Dhaka are surrounded by highly-populated slums in which human waste is directly released into the water. The presence of human gut bacteria links to high levels of antibiotic resistance genes, suggesting that such contamination is driving the presence of these ‘superbugs’ in surface water.

“Interventions aimed at improving access to clean water, sanitation and sewerage infrastructure may thus be important to reduce the risk of antimicrobial resistance spreading in Bangladesh and other LMICs. While levels of antibiotic resistance genes are considerably lower in rural than in urban settings, we found that antibiotics are commonly used in fish farming and further policies need to be developed to reduce their use.”

Infections from antibiotic-resistant bacteria are on the rise globally, but the clinical issues posed by these bacteria are particularly alarming in LMICs, with significant morbidity and mortality. As in other LMICs, multidrug-resistant E. coli has a relatively high prevalence in healthy humans in Bangladesh.

With a population of around 16 million people, Dhaka’s population density ranks among the highest of any megacity, but less than 20% of its households have a sewerage connection.

Urban surface waters in Bangladesh are particularly rich in antibiotic resistance genes, the researchers discovered, with a higher number of them associated with plasmids — vehicles of genetic exchange among bacteria — indicating that they are more likely to spread through the population.

Antibiotic-resistant bacteria that colonise the human gut can be passed into rivers, lakes and coastal areas through the release of untreated wastewater, the overflow of pit latrines during monsoon season or by practices such as open defecation.

Such contaminated environments are often used for bathing, for the washing of clothes and food utensils, thereby risking human gut colonisation by antibiotic-resistant bacteria.

The researchers from the University of Birmingham and the International Centre for Diarrhoeal Disease Research, Bangladesh called for further research to quantify the drivers of antibiotic resistance in surface waters in Bangladesh.

Source: University of Birmingham

Journal information: McInnes, R.S., et al. (2021) Metagenome-Wide Analysis of Rural and Urban Surface Waters and Sediments in Bangladesh Identifies Human Waste as a Driver of Antibiotic Resistance. mSystems. doi.org/10.1128/mSystems.00137-21.

Categories : Antibiotics Obstetrics & Gynaecology PaediatricsTags :

In Utero or Neonatal Antibiotic Exposure Could Lead to Brain Disorders

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Image by Ahmad Ardity from Pixabay
Image by Ahmad Ardity from Pixabay

According to a new study, antibiotic exposure early in life could alter human brain development in areas responsible for cognitive and emotional functions.

The study suggests that penicillin alters the body’s microbiome as well as gene expression, which allows cells to respond to its changing environment, in key areas of the developing brain. The findings, published in the journal iScience, suggest reducing widespread antibiotic use or using alternatives when possible to prevent neurodevelopment problems.
Penicillin and related medicines, such as ampicillin and amoxicillin, are the most widely used antibiotics in children worldwide. In the United States, the average child receives nearly three courses of antibiotics before age 2, and similar or greater exposure rates occur elsewhere.

“Our previous work has shown that exposing young animals to antibiotics changes their metabolism and immunity. The third important development in early life involves the brain. This study is preliminary but shows a correlation between altering the microbiome and  changes in the brain that should be further explored,” said lead author Martin Blaser, director of the Center for Advanced Biotechnology and Medicine at Rutgers.

In the study, mice were exposed to low-dose penicillin in utero or immediately after birth. Researchers found that, compared to the unexposed controls, mice given penicillin had large changes in their intestinal microbiota, with altered gene expression in the frontal cortex and amygdala. These two key brain areas are responsible for the development of memory as well as fear and stress responses.

Increasing evidence links conditions in the intestine to the brain in the ‘gut-brain axis‘. If this pathway is disturbed, it can lead to permanent altering of the brain’s structure and function and possibly lead to neuropsychiatric or neurodegenerative disorders in later childhood or adulthood.

“Early life is a critical period for neurodevelopment,” Blaser said. “In recent decades, there has been a rise in the incidence of childhood neurodevelopmental disorders, including autism spectrum disorder, attention deficit/hyperactivity disorder and learning disabilities. Although increased awareness and diagnosis are likely contributing factors, disruptions in cerebral gene expression early in development also could be responsible.”

Whether it is antibiotics directly affecting brain development or if molecules from the microbiome travelling to the brain, disturbing gene activity and causing cognitive deficits needs to be determined by future studies.

Source: Rutgers University-New Brunswick

Categories : AntibioticsTags :

Disarming a Common Pathogenic Bacterium

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Pseudomonas aeruginosa bacteria. Source: Public Health Imagery Library

Scientists have discovered a gene regulator in a common pathogenic bacterium that can be exploited to drastically reduce its virulence.

Pseudomonas aeruginosa is a gram-negative, aerobic, opportunistic, pathogenic bacterium found in a variety of ecological niches, such as plant roots, stagnant water or even plumbing. Naturally extremely versatile, it can cause acute and chronic infections that are potentially fatal for immunocompromised hosts. P. aeruginosa poses a serious threat in clinical settings, where it can colonise respirators and catheters. Additionally, its adaptability and resistance to many antibiotics make P. aeruginosa infections steadily more difficult to treat. Therefore new antibacterials are urgently needed. 

Scientists from the University of Geneva (UNIGE) in Switzerland have identified a previously unknown regulator of gene expression in this bacterium, without which the infectious power of P. aeruginosa is diminished. This discovery may unlock new developmental pathways to treat this bacteria.

RNA helicases perform essential regulatory functions by binding and unwinding various RNA molecules to perform their functions. RNA helicases are present in the genomes of almost all known living organisms, including bacteria, yeast, plants, and humans; however, they have acquired specific properties depending on the organism in which they are found. “Pseudomonas aeruginosa has an RNA helicase whose function was unknown, but which was found in other pathogens”, explained Martina Valentini,  a researcher leading this research in the Department of Microbiology and Molecular Medicine at UNIGE Faculty of Medicine. “We wanted to understand what its role was, in particular in relation to the pathogenesis of the bacteria and their environmental adaptation.”

A severely reduced virulence

To accomplish this, the researchers took a combined biochemical and molecular genetic approach. “In the absence of this RNA helicase, P. aeruginosa multiplies normally in vitro, both in a liquid medium and on a semi-solid medium at 37°C”, reported Stéphane Hausmann, a researcher associate in the Department of Microbiology and Molecular Medicine at UNIGE Faculty of Medicine and first author of this study. “To determine whether the infection capacity of the bacteria was affected, we had to observe it in vivo in a living organism.”

The scientists then continued their research using Galleria mellonella larvae, a model insect for studying host-pathogen interactions.These larvae can live at temperatures between 5°C and 45°C, which makes it possible to study bacterial growth at different temperatures, including that of the human body. Three groups of larvae were observed, including a control group injected with saline. In the presence of a normal strain of P. aeruginosa, less than 20% survived at 20 hours after infection. In contrast, when P. aeruginosa lacked the RNA helicase gene, over 90% of the larvae remained alive. “The modified bacteria became almost harmless, while remaining very much alive,” says Stéphane Hausmann.

Inhibiting instead of killing

The findings demonstrated that the regulator affects production of several virulence factors in the bacteria. “In fact, this protein controls the degradation of numerous messenger RNAs coding for virulence factors”, summarised Martina Valentini. “From an antimicrobial drug strategy point of view, switching off the pathogen’s virulence factors rather than trying to eliminate the pathogen completely, means allowing the host immune system to naturally neutralise the bacterium and potentially reduces the risk for the development of resistance. Indeed, if we try to kill the bacteria at all costs, the bacteria will adapt to survive, which favours the appearance of resistant strains.”

The Geneva team is continuing its investigations by screening drug molecules to see if any of them can selectively block this protein, and also performing a detailed study in detail on the inhibition mechanisms on which could be based the development of an effective therapeutic strategy.

Source: University of Geneva

Journal reference: Hausmann, S., et al. (2021) The DEAD-box RNA helicase RhlE2 is a global regulator of Pseudomonas aeruginosa lifestyle and pathogenesis. Nucleic Acid Research. doi.org/10.1093/nar/gkab503.

Categories : AntibioticsTags :

Holding off on Antibiotics is Safe and Effective for Patients

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According to an analysis published in BMJ Today, delayed antibiotic prescribing is a safe and effective strategy for most patients with respiratory tract infections.

Delayed antibiotic prescribing—also known as ‘just in case prescribing’—is when patients agree to see whether symptoms settle before collecting a prescription, in order to help reduce antibiotic use.

Delayed prescribing was shown to be associated with a similar duration of symptoms as no antibiotic prescribing and is not likely to lead to poorer symptom control than immediate antibiotic prescribing. In children with immediate antibiotics a slight benefit was seen but this was not judged important enough to justify immediate antibiotic prescribing.

Respiratory tract infections affect the sinuses, throat, airways or lungs and include conditions such as the common cold, sore throat, cough and ear infection. While most improve without treatment, antibiotics are still widely being prescribed for these conditions.

It has been suggested in various clinical trials that delayed antibiotic prescribing for respiratory tract infections is probably safe and effective for most patients, but they were unable to examine different groups of patients or complications.

To address this, an international research team set out to assess the effect of delayed antibiotic prescribing on symptoms for patients with respiratory tract infections in the community.

They used individual patient data on a total of 55 682 patients from nine randomised controlled trials and four observational studies to compare average symptom severity between delayed versus no antibiotic prescribing, and delayed versus immediate antibiotic prescribing.

Most of the studies took place in primary care settings with the average age of study participants ranging from 2.7 to 51.7 years.

The researchers accounted for factors including age, sex, previous duration of illness, severity of symptoms, smoking status and underlying conditions. Average symptom severity was measured two to four days after initial consultation on a seven point scale (ranging from normal to as bad as could be).

The researchers found no difference in symptom severity for delayed versus immediate antibiotics or delayed versus no antibiotics.

Symptom duration was slightly longer in those given delayed versus immediate antibiotics (11.4 v 10.9 days), but was similar for delayed versus no antibiotics.

Complications resulting in hospital admission or death were lower with delayed versus no antibiotics and delayed versus immediate antibiotics, but neither result was statistically significant.

Re-consultation rates were significantly reduced and an increase in patient satisfaction were found for delayed versus no antibiotics, but not for delayed versus immediate antibiotics.

Children under 5 years of age showed slightly more severe symptoms with delayed antibiotics than with immediate antibiotics, but this was not considered to be clinically meaningful, and this was not seen in older age groups.

 hey concluded that delayed antibiotic prescribing “appears to be a safe and effective strategy for most patients, including those in higher risk subgroups.”

This was a large, detailed analysis accounting for differences in study design and quality to reduce bias. The researchers nevertheless pointed out some limitations, being unable to exclude the possibility that other unmeasured factors may have affected their results.

Source: Medical Xpress

Journal information: Beth Stuart et al, Delayed antibiotic prescribing for respiratory tract infections: individual patient data meta-analysis, BMJ (2021). DOI: 10.1136/bmj.n808

Categories : AntibioticsTags :

WHO Says New Antibiotic Treatments are Falling Behind

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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

Categories : AntibioticsTags :

Prevalence of Antibiotic Resistance is Underestimated

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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.

Categories : AntibioticsTags :

Single Water Molecule Is the Key to Macrolide Resistance

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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