Category: Antibiotics

New Antibacterial Molecules Identified

Source: National Cancer Institute on Unsplash

Researchers have identified a new group of molecules with an antibacterial effect against many antibiotic-resistant bacteria. Since the properties of the molecules can easily be altered chemically, the hope is to develop new, effective antibiotics with few side effects. The study appears in PNAS.

Increasing antibiotic resistance is a great concern as few new antibiotics have been developed in the past 50 years.

Most antibiotics work by inhibiting the bacteria’s ability to form a protective cell wall, causing the bacteria to crack (cell lysis). Besides the well-known penicillin, which inhibits enzymes building up the wall, newer antibiotics such as daptomycin or the recently discovered teixobactin bind to a special molecule, lipid II. All bacteria need lipid II as a building block for the cell wall. Antibiotics that bind to Lipid II are usually very large and complex molecules and therefore more difficult to improve with chemical methods. These molecules are in addition mostly inactive against a group of problematic bacteria, which are surrounded by an additional layer, the outer membrane, that hinders penetration of these antibacterials.

“Lipid II is a very attractive target for new antibiotics. We have identified the first small antibacterial compounds that work by binding to this lipid molecule, and in our study, we found no resistant bacterial mutants, which is very promising,” says Birgitta Henriques Normark, professor at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, and one of the article’s three corresponding authors.

For this study, published in PNAS, researchers tested a large number of chemical compounds for their ability to lyse pneumococci – the most common cause of community-acquired pneumonia. After a careful follow-up of active compounds from this screening, the researchers found that a group of molecules called THCz inhibits the formation of the cell wall of the bacterium by binding to lipid II. The molecules could also prevent the formation of the sugar capsule that pneumococci need to escape the immune system and to cause disease.

Small molecules offer several benefits, noted Fredrik Almqvist, professor at Umeå University and one of the corresponding authors: “The advantage of small molecules like these is that they are more easy to change chemically. We hope to be able to change THCz so that the antibacterial effect increases and any negative effects on human cells decrease.”

Laboratory work with THCz showed it has an antibacterial effect against many antibiotic-resistant bacteria, such as methicillin-resistant staphylococci (MRSA), vancomycin-resistant enterococci (VRE), and penicillin-resistant pneumococci (PNSP). An antibacterial effect was also found against gonococci, which causes gonorrhoea, and mycobacteria, bacteria that can cause severe diseases such as tuberculosis in humans. None of the bacteria managed to develop resistance to THCz in a laboratory environment.

“We will now also initiate attempts to change the THCz molecule, allowing it to penetrate the outer cell membrane found in some, especially intractable, multi-resistant bacteria,” says Tanja Schneider, professor at the Institute of Pharmaceutical Microbiology at the University of Bonn and one of the corresponding authors.

Source: Karolinska Institutet

Insects Carry a Range of Antimicrobial-resistant Bacteria

A study published in Nature Microbiology has for the first time provided compelling evidence of connections between antimicrobial-resistant bacteria causing surgical-site infections and insects and other arthropods. Among these bacteria are those with resistance to drug-of-last-resort. 

Antimicrobial resistance (AMR) could render many of the current mainstay and last-resort antibiotics useless, resulting in many more deaths from previously treatable infections. A UN report estimated in 2019 that AMR could lead to ten million deaths per year, and cost the world $100 trillion, by 2050.

“Similar to our experience over the last eighteen months with the pandemic, a problem currently seen from afar will quickly come into focus much closer to home” said Professor Tim Walsh at Oxford University

The report found that:

  • About 20% of the flies, cockroaches, spiders, moths, and ants were carrying carbapenem resistance.
  • Of these, 70-80% were carrying extended spectrum cephalosporin resistance, that is, enzymes that confer resistance to most beta-lactam antibiotics, including penicillins, cephalosporins, and the monobactam aztreonam.
  • Currently there are about 18 million flies to every human, but conservative global warming projections estimate insect and fly population will double if temperatures increase by 1.5 degrees.
  • By 2080 there could be around 50 000 trillion flies carrying carbapenem resistance and spreading AMR across the planet.

“Similar to our experience over the last eighteen months with the pandemic, a problem currently seen from afar will quickly come into focus much closer to home,” said Prof Walsh. “The clinical burden of AMR is most felt in low-middle income countries, but the increase in global temperatures, due to climate change, will result in a significant increase in flies and many other insects and a subsequent increase in the global velocity of antibiotic resistance.” Prof. Tim Walsh, Oxford University.

AMR is a pervasive issue, stretching from hospitals to farming and human waste processing. Resistance can spread within hospitals, communities, farms, and wastewater systems, and domestic animals can share AMR microorganisms with humans.

One tactic is to repurpose previously developed drugs that did not work for humans and use these for animals, buying time for us to develop new drugs.

Another is to rethink hospital prevention and infection control measures, especially in lower- and middle-income countries. Further research into how arthropods disseminate AMR and improving healthcare infrastructure to reduce the spread of AMR by arthropods.

“Most antibiotics currently used on animals are also the same that are used in humans, creating a pool where bacteria can evolve to evade drugs and then reinfect humans,” said Prof Tim Walsh of Oxford University.

“There is no silver bullet when it comes to tackling the worldwide threat of AMR,” he added. “The Ineos Oxford Institute for AMR Research is committed to finding non-human antibiotic therapies and feeds for animals, addressing the increase in AMR in human infections and raising awareness of this hidden threat to human health. But this is a global medical crisis that ultimately will only be resolved with a global response.”

Source: Oxford University

Amoxicillin Flops in Simple Paediatric Chest Infections

Photo by Andrea Piacquadio from Pexels

The largest randomised placebo-controlled trial of the antibiotic amoxicillin for treating paediatric chest infections has found it is little more effective at relieving symptoms than placebo. 

While viruses are believed to cause many chest infections in children, whether antibiotics are effective in treating chest infections in children is still debated. In adults, research has shown that antibiotics are not effective for uncomplicated chest infections.

In the study, published in The Lancet, researchers sought to test whether amoxicillin reduces the duration of moderately bad symptoms in children presenting with uncomplicated (non-pneumonic) lower respiratory tract chest infections in primary care. The trial recruited 432 children aged six months to 12 years-old with acute uncomplicated chest infections from primary care practices, randomised to receive either amoxicillin or a placebo three times a day for seven days. Doctors or nurse-prescribers assessed symptoms at the start of the study and parents, with help from their children where possible, completed a daily symptom diary.

Only a small, non-significant, difference in symptom duration was seen between the two groups: children given the placebo had symptoms which were rated moderately bad or worse for around 6 days on average after seeing the doctor, and those given antibiotics only recovered 13% faster.

This held true even for groups where chest sounds were present, there was a fever, was rated more unwell by a doctor, coughing up phlegm or had a rattly chest, or the child was short of breath.

Just four children in the placebo group and five in the antibiotic group required further assessment at hospital. Parental costs such as leave taken or over-the-counter remedies, were very similar in both groups.

The study lead author, Professor Paul Little, said: “”Children given amoxycillin for chest infections where the doctor does not think the child has pneumonia do not recover much more quickly.

“Indeed, using amoxicillin to treat chest infections in children not suspected of having pneumonia is not likely to help and could be harmful. Overuse of antibiotics, which is dominated by prescribing of antibiotics in primary care, particularly when they are ineffective, can lead to side effects and the development of antibiotic resistance.”

Study co-author Alastair Hay, a GP and University of Bristol professor, added: “The ARTIC PC trial is one of the very few studies to report on the effectiveness of prescribing antibiotics among younger children presenting with chest infections in primary care. It was designed to be able to detect a clinically important 3-day improvement in symptom duration.

“Our results suggest that unless pneumonia is suspected, clinicians should provide ‘safety-netting’ advice such as explaining what illness course to expect and when it would be necessary to re-attend but not prescribe antibiotics for most children presenting with chest infections.”

Source: University of Bristol

Azithromycin Protects Pregnancies in Countries with Malaria

Photo by Hush Naidoo on Unsplash

A review has found that the common antibiotic azithromycin taken during pregnancy reduces low birth weight and premature births in countries where malaria is endemic.

The systematic review of 14 studies in African and Asia, published in The Lancet EClinicalMedicine, found that azithromycin, reduced low birth weight and prematurity but didn’t lower infant deaths, infections and hospital admissions.

Azithromycin, an inexpensive antibiotic widely used to treat chest and ear infections, has been specifically used in the past in pregnancy to treat STIs and, alongside other antimalarial drugs, to prevent adverse consequences of malaria on maternal and foetal outcomes and caesarean wound infections.

Murdoch Children’s Research Institute (MCRI) researcher Dr Maeve Hume-Nixon said it was not clear whether azithromycin would improve perinatal and neonatal outcomes in non-malaria endemic settings, and the potential harm on stillbirth rates needed further investigation.

Dr Hume-Nixon said these findings emphasised the importance of similar MCRI-led research currently being done in Fiji.

“This review found that there was uncertainty about the potential benefits of this intervention on neonatal deaths, admissions and infections, and potential harmful effects on stillbirth despite biological reasons why this intervention may have benefits for these outcomes,” she said.

“Therefore, results from studies like ours underway in Fiji will help to better understand the effect of this intervention on these outcomes.”

The Bulabula MaPei study is a randomised controlled clinical trial testing if azithromycin given to women in labour, prevents maternal and infant infections.

Globally, infections account for 21% of 2.4 million neonatal deaths per year and 52% of all under-five deaths, disproportionately occurring in low- and middle-income countries.

About five million cases of pregnancy-related infections occur in mothers each year as well, resulting in 75 000 maternal deaths.

MCRI Professor Fiona Russell said the large clinical trials in Africa and Asia, along with the MCRI-led trial in Fiji, were likely to inform global policy related to maternal child health and hopefully benefit infants and mothers around the world.

“Administration of azithromycin during labour may be a cheap and simple intervention that could be used to improve neonatal death rates in low and middle-income countries, alongside strengthening of maternal child health services,” she said. “This study, together with other large clinical trials, will add to evidence for the consideration of new international maternal and child health guidelines.”

Source: Murdoch Childrens Research Institute

Human Breast Milk Could Yield Antibiotic Secrets

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

Bacterial Superinfections in COVID Rarer Than Expected

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

Old Antibiotics as New Weapons against Melanoma

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

Untreated Sewage is a Driver of Antibiotic Resistance

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.

In Utero or Neonatal Antibiotic Exposure Could Lead to Brain Disorders

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

Disarming a Common Pathogenic Bacterium

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.