A new study has tricked bacteria into sending death signals to stop the growth of biofilms that lead to deadly infections. The discovery by Washington State University researchers could someday be harnessed as an alternative to antibiotics for treating difficult infections.
Reporting in the journal,Biofilm, the researchers used the messengers, which they named death extracellular vesicles (D-EVs), to reduce growth of the bacterial communities by up to 99.99% in laboratory experiments.
“Adding the death extracellular vesicles to the bacterial environment, we are kind of cheating the bacteria cells,” said Mawra Gamal Saad, first author on the paper and a graduate student in WSU’s Gene and Linda Voiland School of Chemical Engineering and Bioengineering.
“The cells don’t know which type of EVs they are, but they take them up because they are used to taking them from their environment, and with that, the physiological signals inside the cells change from growth to death.”
Bacterial resistance is a growing problem around the world. In the US, at least 2 million infections and 23 000 deaths are attributable to antibiotic-resistant bacteria each year, according to the U.S. Centers for Disease Control.
When antibiotics are used to treat a bacterial infection, some of the bacteria can hide within their tough-to-penetrate biofilm. These subpopulations of resistor cells can survive treatment and are able to grow and multiply, resulting in chronic infections.
“They are resistant because they have a very advanced and well-organised adaptive system,” said Saad.
“Once there is a change in the environment, they can adapt their intracellular pathways very quickly and change it to resist the antibiotics.”
In their new study, the researchers discovered that the extracellular vesicles are key to managing the growth of the protective biofilm.
The vesicles, tiny bubbles from 30 to 50nm or about 2000 times smaller than a strand of hair, shuttle molecules from cells, entering and then re-programming neighbouring cells and acting as a cell-to-cell communications system.
As part of this study, the researchers extracted the vesicles from one type of bacteria that causes pneumonia and other serious infections.
They determined that the bacteria initially secrete vesicles, called growth EVs, with instructions to grow its biofilm, and then later, depending on available nutrients, oxygen availability and other factors, send EVs with new instructions to stop growing the biofilm.
The researchers were able to harness the vesicles with the instructions to stop growth and use them to fool the bacteria to kill off the biofilm at all stages of its growth.
Even when the biofilms were healthy and rapidly growing, they followed the new instructions from the death EVs and died. The death EVs can easily penetrate the biofilm because they are natural products secreted by the bacteria, and they have the same cell wall structure, so the cells don’t recognise them as a foreign enemy.
“By cheating the bacteria with these death EVs, we can control their behaviour without giving them the chance to develop resistance,” said Saad.
“The behavior of the biofilm just changed from growth to death.”
WSU Professor and corresponding author Wen-Ji Dong, who has been studying the vesicles for several years initially thought that all of the bacterial-secreted vesicles would promote cell growth.
The researchers were surprised when they found that older biofilms provided instructions on shutting themselves down.
“So now we’re paying attention to the extracellular vesicles secreted by older biofilms because they have therapeutic potential,” he said.
People with pre-existing conditions in particular can carry resistant germs and suffer from repeated infections for years, according to a study in the scientific journal Nature Communications.
Some bacteria have developed the ability to break down beta-lactam antibiotics like penicillins and cephalosporins, making them ineffective.
Once a patient’s body has been colonised by these resistant bacteria, they can persist for a long time, reports Professor Sarah Tschudin Sutter’s research group at the Department of Clinical Research of the University of Basel and University Hospital Basel.
The researchers looked at a much longer period of time than previous studies and focused on older people with pre-existing conditions, analysing multiple samples taken from over 70 individuals over a period of ten years.
Their key question: whether and how resistant Klebsiella pneumoniae and Escherichia coli bacteria in the body change over this long period and how they differ in various parts of the body.
Recurring illness
DNA analysis indicates that the bacteria initially adapt quite quickly to the conditions in the colonized parts of the body, but undergo few genetic changes thereafter.
The resistant bacteria could still be detected in the patients up to nine years later.
“These patients not only repeatedly become ill themselves, they also act as a source of infection for other people — a reservoir for these pathogens,” says Dr Lisandra Aguilar Bultet, the study’s lead author.
“This is crucial information for choosing a treatment,” explains Professor Tschudin Sutter.
If someone has previously been infected with resistant bacteria and later requires another course of treatment because of a new infection, there is a risk that standard antibiotics will again fail to work.
Transmission of resistance
In addition, the researchers found that in some patients, bacterial strains of the same species, as well as of different species (specifically, Klebsiella pneumoniae and Escherichia coli), share identical genetic mechanisms of resistance through what are known as mobile genetic elements (such as plasmids). The most likely explanation is that they have transmitted these elements to each other.
Hospitals use special protective measures if a patient has been infected with resistant bacteria in the past.
In everyday life, however, it is difficult to reduce the risk of pathogen transmission.
These findings about the bacterial genetic diversity expected to develop in individual patients over time are a valuable basis for future studies to analyse factors found in both bacteria and patients that correlate with duration of colonisation and progression from colonisation to infection.
An international research team has found a number of substances with a dual effect against tuberculosis (TB): They make the bacteria causing the disease less pathogenic for human immune cells whilst boosting the activity of conventional antibiotics. They published their findings in the journal Cell Chemical Biology.
Infectious disease specialist Dr Jan Rybniker and colleagues have identified new, antibiotic molecules that target Mycobacterium tuberculosis and make it less pathogenic for humans.
Diagram by the United States-based National Institute of Allergy and Infectious Diseases showing the medicine options for drug-resistant tuberculosis. (Via Flickr, CC BY 2.0 Deed)
In addition, some of the discovered substances may allow for a renewed treatment of tuberculosis with available medications – including strains of the bacterium that have already developed drug resistance.
Although treatable with antibiotics, it still ranks among the infectious diseases that claim the most lives worldwide: According to the World Health Organization (WHO), only COVID was deadlier than TB in 2022. The disease also caused almost twice as many deaths as HIV/AIDS. More than 10 million people continue to contract TB every year, mainly due to insufficient access to medical treatment in many countries.
Limited targets
Multidrug-resistant tuberculosis is emerging especially in eastern Europe and Asia. That is of particular concern to researchers because like all bacteria that infect humans, Mycobacterium tuberculosis possesses only a limited number of targets for conventional antibiotics.
That makes it increasingly difficult to discover new antibiotic substances in research laboratories.
Working together with colleagues from the Institute Pasteur in Lille, France, and the German Center for Infection Research (DZIF), the researchers at University Hospital Cologne have now identified an alternative treatment strategy for the bacterium.
The team utilized host-cell-based high-throughput methods to test the ability of molecules to stem the multiplication of bacteria in human immune cells: From a total of 10,000 molecules, this procedure allowed them to isolate a handful whose properties they scrutinized more closely in the course of the study.
Two-pronged attack
Ultimately, the researchers identified virulence blockers that utilise target structures that are fundamentally distinct from those targeted by classical antibiotics.
“These molecules probably lead to significantly less selective pressure on the bacterium, and thus to less resistance,” said Jan Rybniker, who heads the Translational Research Unit for Infectious Diseases at the Center for Molecular Medicine Cologne (CMMC) and initiated the study.
In deciphering the exact mechanism of action, the researchers also discovered that some of the newly identified chemical substances are dual-active molecules.
Thus, they not only attack the pathogen’s virulence factors, but also enhance the activity of monooxygenases — enzymes required for the activation of the conventional antibiotic ethionamide.
Ethionamide is a drug that has been used for many decades to treat TB. It is a so-called prodrug, a substance that needs to be enzymatically activated in the bacterium to kill it. Therefore, the discovered molecules act as prodrug boosters, providing another alternative approach to the development of conventional antibiotics.
In cooperation with the research team led by Professor Alain Baulard at Lille, the precise molecular mechanism of this booster effect was deciphered.
Thus, in combination with these new active substances, drugs that are already in use against tuberculosis might continue to be employed effectively in the future.
The discovery offers several attractive starting points for the development of novel and urgently needed agents against tuberculosis.
“Moreover, our work is an interesting example of the diversity of pharmacologically active substances. The activity spectrum of these molecules can be modified by the smallest chemical modifications,” Rybniker added.
However, according to the scientists it is still a long way to the application of the findings in humans, requiring numerous adjustments of the substances in the laboratory.
Antibiotic-resistant bacteria are a growing global problem, but of the solution may lie in copying the bacteria’s own weapons. Researchers in the Norwegian city of Tromsø has found a new bacteriocin, in a very common skin bacterium, which they describe in Microbiology Spectrum. Bacteriocin inhibits the growth of antibiotic-resistant bacteria that are often the cause of disease and can be difficult to treat.
One million deaths each year
The fact that we have medicines against bacterial infections is something many people take for granted. But increasing resistance among bacteria means that more and more antibiotics do not work. When the bacteria become resistant to the antibiotics we have available, we are left without a treatment option for very common diseases. Over one million people die each year as a result of antibiotic resistance.
The first step in developing new antibiotics is to look for substances that inhibit bacterial growth.
Sami name for an exciting discovery
The research group for child and youth health at UiT The Arctic University of Norway has studied substances that the bacteria themselves produce to inhibit the growth of competitors. These substances are called bacteriocins. Through the work, they have discovered a new bacteriocin, in a very common skin bacterium. Bacteriocin inhibits the growth of antibiotic-resistant bacteria that can be difficult to treat with common antibiotics.
The researchers have called the new bacteriocin Romsacin, after the Sami name for Tromsø, Romsa. The hope is that Romsacin can be developed into a new medicine for infections for which there is currently no effective treatment.
Long way to go
At the same time, researcher Runa Wolden at the Department of Clinical Medicine at UiT emphasizes that there is a long way to go before it is known whether Romsacin will be developed and taken into use as a new medicine. Because that’s how it is with basic research; you cannot say in advance when someone will make use of the results you produce.
“This discovery is the result of something we have been researching for several years. Developing Romsacin – or other promising substances – into new antibiotics is very expensive and can take 10-20 years,” says Wolden, who is part of the research group for child and youth health.
Effective against bacterial types
Before new antibiotics can be used as medicines, one needs to make sure that they are safe to use. Currently, researchers do not know how the bacteriocin works in humans. A further process will involve comprehensive testing, bureaucracy and marketing.
“This naturally means that there is a long way to go before we can say anything for sure. What we already know, however, is that this is a new bacteriocin, and that it works against some types of bacteria that are resistant to antibiotics. It’s exciting,” says Wolden.
The new bacteriocin is produced by a bacterium called Staphylococcus haemolyticus. The bacteriocin is not produced by all S. haemolyticus, but by one of the 174 isolates that the researchers have available in the freezer.
“We couldn’t know that before we started the project, and that’s one of the things that makes research fun,” says Wolden.
She says that ten years ago the researchers collected bacterial samples from healthy people when they wanted to compare S. haemolyticus in healthy people with those found in patients in hospital.
“Subsequently, we have done many experiments with these bacteria, and this is the result from one of our projects,” says Wolden.
A study published in Nature Microbiology has uncovered startling connections between micronutrient deficiencies and the composition of gut microbiomes in early life that could help explain why resistance to antibiotics has been rising across the globe.
A University of British Colombia team investigated how deficiencies in crucial micronutrients such as vitamin A, B12, folate, iron, and zinc affected the community of bacteria, viruses, fungi and other microbes that live in the digestive system.
They discovered that these deficiencies led to significant shifts in the gut microbiome of mice – most notably an alarming expansion of bacteria and fungi known to be opportunistic pathogens.
Importantly, mice with micronutrient deficiencies also exhibited a higher enrichment of genes that have been linked to antibiotic resistance.
“Micronutrient deficiency has been an overlooked factor in the conversation about global antibiotic resistance,” said Dr. Paula Littlejohn, a postdoctoral research fellow with UBC’s department of medical genetics and department of pediatrics, and the BC Children’s Hospital Research Institute. “This is a significant discovery, as it suggests that nutrient deficiencies can make the gut environment more conducive to the development of antibiotic resistance, which is a major global health concern.”
Bacteria naturally possess these genes as a defence mechanism. Certain circumstances, such as antibiotic pressure or nutrient stress, cause an increase in these mechanisms. This poses a threat that could render many potent antibiotics ineffective and lead to a future where common infections could become deadly.
Antibiotic resistance is often attributed to overuse and misuse of antibiotics, but the work of Dr. Littlejohn and her UBC colleagues suggests that the ‘hidden hunger’ of micronutrient deficiencies is another important factor.
“Globally, around 340 million children under five suffer from multiple micronutrient deficiencies, which not only affect their growth but also significantly alter their gut microbiomes,” said Dr. Littlejohn. “Our findings are particularly concerning as these children are often prescribed antibiotics for malnutrition-related illnesses. Ironically, their gut microbiome may be primed for antibiotic resistance due to the underlying micronutrient deficiencies.”
The study offers critical insights into the far-reaching consequences of micronutrient deficiencies in early life. It underscores the need for comprehensive strategies to address undernutrition and its ripple effects on health. Addressing micronutrient deficiencies is about more than overcoming malnutrition, it may also be a critical step in fighting the global scourge of antibiotic resistance.
Newly announced results of a pivotal phase 3 trial have demonstrated the effectiveness of a new one-dose treatment for gonorrhoea. The medicine, called zoliflodacin, is the first new drug developed to treat gonorrhoea in over 30 years. More than half of the 930 patients included in the trial were from South Africa, including women, adolescents, and people living with HIV.
Zoliflodacin, which was shown to be non-inferior to (as good as) the currently used treatment in treating uncomplicated gonorrhoea, provides an important new tool to combat rising rates of drug resistant gonorrhoea. It was found to be generally well tolerated and there were no serious adverse events or deaths recorded in the trial. So far, only top line results have been shared in a media release and the findings have not yet been published in a medical journal. (You can see some technical details of the study design on ClinicalTrials.gov)
The World Health Organization raised the alarm about increasing rates of drug resistant gonorrhoea in 2017, noting the emergence of cases of untreatable gonorrhoea resistant to all available antibiotics. According to the United States Centers for Disease Control and Prevention “medication to treat gonorrhoea has been around for decades, but the bacteria has grown resistant to nearly every drug ever used to treat it”. They say: “only one class of antibiotics known as cephalosporins remains to treat the infection”.
As a drug from a new class of antibiotics, zoliflodacin, offers a new potential treatment for patients whose gonorrhoea was previously untreatable, as well as a new tool for safeguarding the ongoing effectiveness of currently available antibiotics.
How zoliflodacin may change gonorrhoea treatment
Professor Sinead Delany-Moretlwe, Director of Research for Wits RHI and the National Principal Investigator for the trial in South Africa, told Spotlight that while zoliflodacin may be used to treat drug resistant gonorrhoea, it also provides an attractive new treatment option for first-line treatment of gonorrhoea in some countries (in other words, gonorrhoea that is not resistant to other treatments).
Zoliflodacin, which is taken as a single oral dose, is simpler to administer than the current standard of care, which involves a combination of injectable ceftriaxone and oral azithromycin. Removing the need for an injection could simplify the administration of gonorrhoea treatment and improve its uptake.
Using zoliflodacin as first-line gonorrhoea treatment can also help safeguard the ongoing effectiveness of cephalosporins (including ceftriaxone), according to Delany-Moretlwe, which she adds are needed not just for treatment of gonorrhoea, but also other infections.
According to Delany-Moretlwe, because zoliflodacin is the first of a new class of antibiotics with novel mechanisms of action and without existing cross resistance, the hope is that widespread use of zoliflodacin as first-line gonorrhoea treatment will slow the emergence of resistance compared with the medicines currently being used.
The Global Antibiotic Research and Development Partnership (GARDP), a non-profit that sponsored the trial, points out that: “Antimicrobial resistance [AMR] has been around for millions of years, long before the first man-made antibiotics. So, drug-resistant bacteria are inevitable and will eventually affect all antibiotics”. They state: “to beat AMR we need a steady supply of new antibiotics to be developed that are effective against drug-resistant bacteria, particularly for priority pathogens that have the greatest public health impact.”
Gonorrhoea in South Africa
South Africa has incredibly high rates of gonorrhoea, with an estimated 2 million new cases annually. While data on rates of drug resistance in the country is limited, the data that is available indicates that ceftriaxone resistance in the country is low, but azithromycin resistance is concerningly high in some parts of the country.
As there is no routine screening for gonorrhoea in South Africa, linkage to treatment remains a challenge. Currently, diagnosis is largely done through symptomatic reporting by patients. But this approach misses many cases as some patients do not self-report symptoms and some cases of gonorrhoea are asymptomatic.
In 2022, the Southern African HIV Clinicians Society released new guidelines for the management of sexually transmitted infections which called for provider-initiated symptomatic screening and provider-initiated diagnostic screening in high-risk populations.
The country’s new National Strategic Plan on HIV, TB and STIs has set a target to increase the number of pregnant women tested for gonorrhoea from 10% in 2023 to 80% by 2028 and has committed to implementing diagnostic testing in other priority populations, including adolescent girls and young women.
How will new gonorrhoea treatments be commercialised?
Zoliflodacin was developed by GARDP in collaboration with the company Innoviva Specialty Therapeutics. According to GARDP, it holds the rights to register and commercialise zoliflodacin in more than three-quarters of the world’s countries, including all low-income countries, most middle-income countries, and several high-income countries. While, Entasis Therapeutics Limited, an affiliate of Innoviva Specialty Therapeutics, “retains the commercial rights for zoliflodacin in the major markets in North America, Europe, Asia-Pacific, and Latin America”.
South Africa is one of the countries in which GARDP holds the rights to register and commercialise zoliflodacin. It is anticipated that this will be done through selection and licensing of companies to manufacture and supply zoliflodacin in South Africa and other countries where GARDP holds commercialisation rights.
GARDP recently launched a request for proposals from partners that are interested in commercialising zoliflodacin. GARDP has also signed a memorandum of understanding with two generic producers to explore opportunities to commercialise the medicine in low-and-middle-income countries.
While the price that will be offered by commercial partners for the product remains to be seen, it is anticipated that products will be made available at affordable prices in line with GARDP’s goal to ensure that “all GARDP products are available, affordable, and appropriately used across populations that need them”.
“This is the first study to address a World Health Organization priority pathogen that has been sponsored and led by a non-profit organization,” says GARDP.
“This demonstrates that GARDP’s model can play a crucial role in helping to fix the public health failure at the heart of the global AMR crisis,” says Professor Glenda Gray, GARDP board member and President of the South African Medical Research Council.
SA involvement
According to GARDP, South Africa had the highest number of participants in the global trial, across six sites in four provinces: Wits RHI in Hillbrow, Johannesburg; the Desmond Tutu HIV Foundation in Masiphumelele, Cape Town; Setshaba Research Centre in Soshanguve, Gauteng; the SAMRC’s clinical research sites in Botha’s Hill and Tongaat in KwaZulu-Natal; and Ndlovu Research Centre in Groblersdal, Limpopo.
“We have also been able to leverage our HIV experience to build capacity for trials of novel STI technologies, a previously neglected area. Undertaking this vital work on a new treatment for gonorrhoea has also given us the opportunity to focus sharply on the local situation in South Africa,” says Delany-Moretlwe.
High rates of antibiotic resistance now meant that drugs to treat common infections in children and babies are no longer effective in large parts of the world, according to findings published in Lancet South East Asia.
The University of Sydney led study found many antibiotics recommended by the World Health Organization (WHO) had less than 50% effectiveness in treating childhood infections such as pneumonia, sepsis (bloodstream infections) and meningitis. The findings show global guidelines on antibiotic use are outdated and need updates.
The most seriously affected regions are in South-East Asia and the Pacific, including neighbouring Indonesia and the Philippines, where thousands of unnecessary deaths in children resulting from antibiotic resistance occur each year.
The WHO has declared antimicrobial resistance (AMR) is one of the top 10 global public health threats facing humanity. In newborns, an estimated three million cases of sepsis occur globally each year, with up to 570 000 deaths: many of these are due to lack of effective antibiotics to treat resistant bacteria.
The findings add to mounting evidence that common bacteria responsible for sepsis and meningitis in children are often resistant to prescribed antibiotics.
The research reveals the urgent need for global antibiotic guidelines to be updated, to reflect the rapidly evolving rates of AMR. The most recent guideline from The World Health Organization was published in 2013.
The study found one antibiotic in particular, ceftriaxone, was likely to be effective in treating only one in three cases of sepsis or meningitis in newborn babies. Ceftriaxone is also widely used in Australia to treat many infections in children, such as pneumonia and urinary tract infections.
Another antibiotic, gentamicin, was found likely to be effective in treating fewer than half of all sepsis and meningitis cases in children.
Gentamicin is commonly prescribed alongside aminopenicillins, which the study showed also has low effectiveness in combating bloodstream infections in babies and children.
Lead author Dr Phoebe Williams from the University’s School of Public Health and Sydney Infectious Diseases Institute is an infectious disease specialist whose research focuses on reducing AMR in high-burden healthcare settings in Southeast Asia.
She also works as a clinician in Australia. Dr Williams says there are increasing cases of multidrug-resistant bacterial infections in children around the world.
AMR is more problematic for children than adults, as new antibiotics are less likely to be trialled on, and made available to, children.
Dr Williams says the study should be a wake-up call for the whole world, including Australia.
“We are not immune to this problem – the burden of anti-microbial resistance is on our doorstep,” she said.
“Antibiotic resistance is rising more rapidly than we realise. We urgently need new solutions to stop invasive multidrug-resistant infections and the needless deaths of thousands of children each year.”
The study analysed 6,648 bacterial isolates from 11 countries across 86 publications to review antibiotic susceptibility for common bacteria causing childhood infections.
Dr Wiliams said the best way to tackle antibiotic resistance in childhood infections is to make funding to investigate new antibiotic treatments for children and newborns a priority.
“Antibiotic clinical focus on adults and too often children and newborns are left out. That means we have very limited options and data for new treatments.”
Dr Williams is currently looking into an old antibiotic, fosfomycin, as a temporary lifeline to treat multidrug-resistant urinary tract infections in children in Australia.
She is also working with the WHO’s Paediatric Drug Optimisation Committee to ensure children have access to antibiotics to treat multidrug-resistant infections as soon as possible, to reduce deaths due to AMR among children.
“This study reveals important problems regarding the availability of effective antibiotics to treat serious infections in children,” says senior author Paul Turner, director of the Cambodia Oxford Medical Research Unit at Angkor Hospital for Children, Siem Reap and professor of paediatric microbiology at the University of Oxford, UK.
“It also highlights the ongoing need for high quality laboratory data to monitor the AMR situation, which will facilitate timely changes to be made to treatment guidelines.”
A study published in PLOS Biology reveals that different strains of Escherichia coli can outcompete one another to take over the gut. The researchers found that a particular strain, known as MDR ST131, can readily colonise new hosts, even if those hosts are already have commensal E.coli in their healthy gut.
The international team, led by experts at the University of Birmingham, used a mouse model to help understand why strains of E.coli that live in a healthy gut are rapidly overtaken of when challenged with a multi-drug resistant strain.
Lead author Professor Alan McNally, from the Institute of Microbiology and Infection at the University of Birmingham, commented: “Antibiotic resistance has been hailed as one of the biggest health problems of our time by the World Health Organisation. There are further problems looming unless we get a better understanding of what is happening so that further drug resistance can be halted in its tracks.
“Scientists have long questioned what makes certain types of E. coli successful multi-drug resistant pathogens. It seems that extra-intestinal pathogenic E. coli, which cause urinary tract and bloodstream infections, are particularly successful when it comes to developing resistance and are therefore especially tricky to treat. Our study provides evidence that certain types of E. coli are more prone to develop antibiotic resistance than others.”
According to previous research, multi-drug resistance alone is not sufficient to drive strains to complete dominance. This most recent study demonstrates that regardless of multi-drug resistant status, certain types of E.coli will outcompete others to live in the human gut.
The work was completed in parts. First, both multi-drug resistant and non-resistant gut-dwelling E. coli were found to easily colonise a mammalian gut. In a second part of the study, the multi-drug resistant strain was found to efficiently displace an already established gut-dwelling E. coli from the mouse intestinal tract. The study provided further details to demonstrate that multidrug resistant lineages of extraintestinal E. coli have particular genetic differences that appear to give them a competitive advantage.
Successful strains of E.coli need to be able to spread between individuals or from the environment into individual hosts. The new study demonstrates that a particular strain, known as MDR ST131, can readily colonise new hosts, even if those hosts are already have E. coli in their healthy gut.
A human neutrophil interacting with Klebsiella pneumoniae (pink), a multidrug–resistant bacterium that causes severe hospital infections.
Credit: National Institute of Allergy and Infectious Diseases, National Institutes of Health
New “hypervirulent” strains of the bacterium Klebsiella pneumoniae have emerged in healthy people in community settings, prompting researchers to investigate how the human immune system defends against infection by it. After exposing the strains to components of the human immune system in vitro, they found that some strains were more likely to survive in blood and serum than others, and that neutrophils are more likely to ingest and kill some strains than others. The study, published in mBio, was led by researchers at NIH’s National Institute of Allergy and Infectious Diseases (NIAID).
“This important study is among the first to investigate interaction of these emergent Klebsiella pneumoniae strains with components of human host defence,” Acting NIAID Director Hugh Auchincloss, MD, said. “The work reflects the strength of NIAID’s Intramural Research Program. Having stable research teams with established collaborations allows investigators to draw on prior work and quickly inform peers about new, highly relevant public health topics.”
K. pneumoniae was identified over a hundred years ago as a cause of serious, often fatal, human infections, mostly in already ill or immunocompromised patients and especially if hospitalised. Over decades, some strains developed resistance to multiple antibiotics. Often called classical Klebsiella pneumoniae (cKp), this bacterium ranks as the third most common pathogen isolated from hospital bloodstream infections. Certain other Klebsiella pneumoniae strains cause severe infections in healthy people in community settings (outside of hospitals) even though they are not multidrug-resistant. They are known as hypervirulent Klebsiella pneumoniae, or hvKp. More recently, strains with both multidrug resistance and hypervirulence characteristics, so-called MDR hvKp, have emerged in both settings.
NIAID scientists have studied this general phenomenon before. In the early 2000s they observed and investigated virulent strains of methicillin-resistant Staphylococcus aureus (MRSA) bacteria that had emerged in US community settings and caused widespread infections in otherwise healthy people.
Now, the same NIAID research group at Rocky Mountain Laboratories in Hamilton, Montana, is investigating similar questions about the new Klebsiella strains, such as whether the microbes can evade human immune system defenses. Their findings were unexpected: the hvKp strains were more likely to survive in blood and serum than MDR hvKp strains. And neutrophils had ingested less than 5% of the hvKp strains, but more than 67% of the MDR hvKp strains – most of which were killed.
The researchers also developed an antibody serum specifically designed to help neutrophils ingest and kill two selected hvKp and two selected MDR hvKp strains. The antiserum worked, though not uniformly in the hvKp strains. These findings suggest that a vaccine approach for prevention/treatment of infections is feasible.
Based on the findings, the researchers suggest that the potential severity of infection caused by MDR hvKp likely falls in between the classical and hypervirulent forms. The work also suggests that the widely used classification of K. pneumoniae into cKp or hvKp should be reconsidered.
The researchers also are exploring why MDR hvKp are more susceptible to human immune defences than hvKp: Is this due to a change in surface structure caused by genetic mutation? Or perhaps because combining components of hypervirulence and antibiotic resistance reduces the bacterium’s ability to replicate and survive in a competitive environment.
As a next step, the research team will use mouse models to determine the factors involved in MDR hvKp susceptibility to immune defences. Ultimately, this knowledge could inform treatment strategies to prevent or decrease disease severity.
A US study found that, despite prescriptions for the antibiotic ciprofloxacin dropping by two-thirds between 2015 and 2021, the rates of ciprofloxacin-resistant E. coli bacteria circulating in the community did not decline.
In fact, a study of women over age 50 who had not taken any antibiotics for at least a year discovered that the incidence of gut-colonising ciprofloxacin-resistant E. coli actually increased. About 1 in 5 women in the study were affected.
Scientists at the University of Washington School of Medicine, Kaiser Permanente Washington Health Research Institute and Seattle Children’s Hospital conducted the study. Their findings appear in Communications Medicine.
Their results are consistent with theoretical models indicating that, once a drug-resistant form of E.coli emerges, it will continue to spread by taking up long-term residence in individuals’ gut microbiomes. E. coli is among an alarming number of disease-causing bacteria that have become resistant to several types of antibiotics. Resistance means that the antibiotics can’t kill the bacteria.
Pathogenic E. coli from the gut occasionally enters the urinary tract opening and causes infections. The female pelvic anatomy makes women more vulnerable to these mobile bacteria. Postmenopausal women are especially susceptible to severe, drug-resistant infection. Some drug-resistant E. coli infections are associated with considerable risk of hospitalization and death from sepsis.
Urinary tract infections from antibiotic-resistant E. coli can be frustrating to treat, even with third-generation cephalosporins, the newer types of antibiotics that are being prescribed more frequently for some populations of patients. Resistance to cephalosporins among ciprofloxacin-resistant E. coli also rose between 2015 and 2021.
Ciprofloxacin and similar drugs in its class were once the most prescribed antibiotic for urinary tract infections. In 2015, recommendations from the Centers for Disease Control and Prevention, Food and Drug Administration and Infectious Disease Society of America discouraged broad use of this class of drugs for uncomplicated urinary tract infections, partly due to rising resistance.
“However, it appears to be questionable whether a reduction in antibiotic use can be effective in reducing the rates of resistance in E. coli infections,” the research paper’s authors noted.
“Evidence from studies such as this one may be changing lots of paradigms on how to fight the rise in antibiotic resistance,” said physician scientist Dr. Evgeni V. Sokurenko, professor of microbiology at the University of Washington School of Medicine, who headed this latest research.
In the study, the scientists examined participants’ positive samples to determine which antibiotic-resistant strains of E. coli were present.
They found that the rate of a particularly virulent strain, ST1193, rose during the study period. Together with E. coli strain ST131-H30, these strains are the major causes of a global pandemic of multi-drug-resistant urinary tract infections among all women.
If ST1193 makes its home in more people’s guts, the situation could lead to more urinary tract infections with this more virulent strain, regardless of the curbing of fluoroquinolones prescriptions.
Another strain with a troubling increase in the participant samples was ST69, known to more frequently cause urinary tract infections in children.
tize discovering better ways to control drug-resistant E. coli’s ability to colonize the gut before it causes these infections, the authors wrote. They mentioned potential strategies of deploying probiotic bacteria and anti-bacterial viruses (bacteriophages).
The researchers added that these approaches might be offered to high-risk patients or deployed against the most clinically relevant strains. More investigation is needed on the epidemiology and ecology of antibiotic-resistant gut E. coli, they said, to help determine how these bacteria skillfully colonize human guts and how to target them most effectively to reduce antibiotic-resistant infections.
