Tag Archives: #antibiotics

Antibiotics May Help To Treat Melanoma (Medicine)

Some antibiotics appear to be effective against a form of skin cancer known as melanoma. Researchers at KU Leuven, Belgium, examined the effect of these antibiotics on patient-derived tumours in mice. Their findings were published in the Journal of Experimental Medicine.

Researchers from KU Leuven may have found a new weapon in the fight against melanoma: antibiotics that target the ‘power plants’ of cancer cells. These antibiotics exploit a vulnerability that arises in tumour 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 tumour mass at a later stage” explains cancer researcher and RNA biologist Eleonora Leucci (KU Leuven). “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 tumours into mice, which were then treated with antibiotics – either as the only treatment or in combination with existing anti-melanoma therapies. Leucci: “The antibiotics quickly killed many cancer cells and could thus be used to buy the precious time needed for immunotherapy to kick in. In tumours that were no longer responding to targeted therapies, the antibiotics extended the lifespan of – and in some cases even cured – the mice.”

The researchers worked with antibiotics that are now, because of rising antibiotic resistance, only rarely used in bacterial infection. However, this resistance has no effect on the efficacy of the treatment in this study, explains Leucci. “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 shouldn’t start experimenting, warns 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-sensitised 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.”

This press release covers fundamental research. While this type of research may be the first step towards new treatments, the development process takes years. Therefore, a breakthrough in research is not the same as a breakthrough in medicine. If you have any questions or concerns about your health, please contact your local doctor for medical advice.

Reference: Roberto Vendramin, Vicky Katopodi, Sonia Cinque, Angelina Konnova, Zorica Knezevic, Sara Adnane, Yvessa Verheyden, Panagiotis Karras, Ewout Demesmaeker, Francesca M. Bosisio, Lukas Kucera, Jan Rozman, Ivan Gladwyn-Ng, Lara Rizzotto, Erik Dassi, Stefania Millevoi, Oliver Bechter, Jean-Christophe Marine, Eleonora Leucci; Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma. J Exp Med 6 September 2021; 218 (9): e20210571. doi: https://doi.org/10.1084/jem.20210571

Provided by KU Leuven

Common Antibiotic Found Useful in Accelerating Recovery in Tuberculosis Patients (Medicine)

Trial in 30 patients shows that doxycycline, in combination with tuberculosis treatment, reduced lung cavity size and increased other markers of recovery

Globally, an estimated 10 million people develop tuberculosis (TB) each year and the disease remains a leading cause of death from a single infectious agent. Standard short-course anti-TB treatment still requires a regimen of at least six months of antimicrobial drugs, and drug-resistant TB is an increasing public health threat. Even after the traces of TB disease are quashed, patients often suffer from significant sequelae, such as lung scarring. TB survivors have approximately three to four times greater mortality than their local population.

In pulmonary TB, the most common form of active TB disease, the Mycobacterium tuberculosis bacteria causes the formation of sites of high bacterial load, known as cavities. These cavities are poorly penetrated by TB drugs. After TB treatment is complete, there is likely to be tissue damage within the lungs that can lead to further lung problems such as permanent respiratory dysfunction leading to difficulty in breathing, stiffness in the lungs and bronchiectasis, which can make people cough up blood.

Researchers from NUS Yong Loo Lin School of Medicine’s Infectious Diseases Translational Research Programme have discovered that the use of a common antibiotic, doxycycline, in combination with TB drug treatment, reduces the size of lung cavities and accelerates markers of lung recovery.

In the Phase 2 double-blind trial conducted at the National University Hospital and TB Control Unit, the treatment was found to be safe, with side effects similar to patients on placebo pills. The study shows promise in delivering a new standard-of-care which can potentially prevent long term complications and the study team is seeking funds for a fully-powered larger scale Phase 3 trial to verify these findings.

“Pulmonary TB patients tend to suffer from lung damage after TB, which is associated with mortality, and poorer quality of life. Doxycycline is a cheap and widely available antibiotic that can decrease lung damage, and potentially improve quality of life for these patients,” said Assistant Professor Catherine Ong, Principal Investigator of the study and member of the Infectious Diseases Translational Research Programme (TRP) at NUS Medicine. The study findings were published in the Journal of Clinical Investigation.

Professor Paul Tambyah, who was also involved in the study and is Deputy Director of the Infectious Diseases TRP commented, “While we have been able to successfully treat most cases of TB for the last few decades, we have seen many people suffer the complications of the lung damage from the original TB infection. If this common drug, doxycycline, can help prevent the complications of “Long TB” (to use a term currently in vogue), this will really help a lot of patients in Singapore and worldwide.”

The Infectious Diseases TRP aims to provide a holistic, patient-centric approach to infectious diseases that are relevant to Singapore and the region. The Programme focuses on programmatic research areas including pathogen evolution and transmission, host-microbe interactions and vaccine and therapeutics development.

The study, “Doxycycline host-directed therapy in human pulmonary tuberculosis”, published in J Clin Invest. On June 2021. https://doi.org/10.1172/JCI141895.

Provided by National University of Singapore

Very High Use Of Antibiotics In COVID-19 Treatment Could Be Reduced (Medicine)

The very high use of antibiotics in patients hospitalised with COVID-19 is often not necessary, and risks worsening global antimicrobial resistance.

New research led by the University of Glasgow as part of the ISARIC (International Severe Acute Respiratory and emerging Infections Consortium) WHO Clinical Characterisation Protocol UK (CCP-UK), found that antibiotic use was very high in hospitalised COVID-19 patients in the UK during the first wave despite confirmed bacterial infection being uncommon.

The study, which is published in The Lancet Microbe and was conducted in collaboration with the Universities of Edinburgh and Liverpool and Imperial College London, found that overall 85% of COVID-19 patients received one or more antibiotics during their hospital admission, with the highest use in critical care, while 37% of patients were prescribed antibiotics prior to admission.

There was high use of broad-spectrum antibiotics – those active against a very wide range of bacteria – and evidence that this could be reduced by using more targeted but equally appropriate alternatives. Importantly, confirmed bacterial infections in people with COVID-19 were uncommon, especially when first admitted to hospital, so a more restrictive approach to using antibiotics would be safe and should be encouraged. Most of the bacteria identified represented secondary infections which began more than 48 hours from admission.

Researchers also found that secondary infections occurring after hospitalisation were not specific to COVID-19 infection and more in keeping with hospital-associated infections and particularly those infections typically seen in intensive care units. These findings will help to inform most appropriate approach to antibiotic prescribing in patients with COVID-19 suspected of having a bacterial infection.

Although co-infections were rarely observed during the first wave of the pandemic there remains a need to monitor hospitalised patients in light of increased use of steroids and other COVID-19 treatments, which may increase susceptibility to bacterial infection. However, the researchers argue that over-prescription of antibiotics and particularly broad-spectrum antibiotics in the majority of hospitalised patients with COVID-19 raises significant concern regarding the potential detrimental impact on antimicrobial resistance globally. The importance of efforts to safely reduce and control antibiotic prescribing in COVID-19 should not be underestimated.

Dr Antonia Ho, lead author of the study from the MRC-University of Glasgow Centre for Virus Research, said: “Until now, a detailed understanding of the nature of bacterial co-infections identified in patients with COVID-19, and the frequency and types of antibiotics these patients have been prescribed has been lacking. This study demonstrates the very high antibiotic use we see in hospitalised COVID-19 patients may not be necessary, indeed it may contribute to antimicrobial resistance.

“While some COVID-19 patients will require antibiotics, mostly for secondary infections which develop after admission to hospital, our data shows that not all COVID-19 patients should be prescribed antibiotics. The longer someone is in hospital, particularly if they are in critical care, the more vulnerable they are to develop secondary infections, and these should continue to be monitored. However, the bugs we identified are similar to those found in patients with hospital-acquired infection, and not specific to COVID-19.”

Dr. Clark Russell, a Clinical Lecturer at the University of Edinburgh said: “Bacterial chest and bloodstream infections are uncommon complications of COVID-19. This work identifies which bacteria tend to cause these infections when they do occur, helping clinicians to make a more informed choice about the best antibiotics to give people when needed.”

Prof Calum Semple, Co-Lead of the study said, “We only have safe surgery and medical cures for many life threatening conditions because antibiotics were discovered and mostly still work.  Overuse of antibiotics needs to be avoided to prevent emergence of resistance.  When the current threat from COVID-19 subsides, the problem of antimicrobial resistance will remain a threat.”

Bacterial co-infections and secondary infections are commonly identified in severe influenza (up to a quarter of cases) and other severe respiratory viral infections, where they are also associated with increased morbidity and mortality. Current national and international COVID-19 guidelines vary in their recommendations on non-targeted antibiotic use. UK guidelines advise against antibiotic use when the respiratory tract infection is thought to be due to COVID-19, without specific evidence of bacterial infection.

The paper ‘Co-infections, secondary infections, and antimicrobial usage in hospitalised patients with COVID-19 during the first wave from the ISARIC WHO CCP-UK study: a prospective, multicentre cohort study’ is published in the Lancet Microbe. The work was funded by The Medical Research Council (MRC), National Institute for Health Research (NIHR) and by the NIHR Health Protection Research Unit (HPRU), Wellcome, and the Bill and Melinda Gates Foundation.

Provided by University of Glasgow

Antibiotics No Help For Mysterious Lung-scarring Disease, Large Trial Finds (Medicine)

Doctors have hoped that antibiotics could benefit patients with chronic lung diseases, but a new study has found no benefit for patients with life-threatening idiopathic pulmonary fibrosis in preventing hospitalization or death.

While there were no statistical benefits for patients with the lung-scarring disease, the new research will prevent unnecessary antibiotic use that could contribute to the growing problem of antibiotic resistance. The nationwide clinical trial – believed to be the largest idiopathic pulmonary fibrosis trial ever conducted – also collected biological samples that will advance the understanding and treatment of the mysterious and ultimately fatal illness.

“We were certainly disappointed in the results. But we remain hopeful that in further downstream analyses, we may yet find groups of patients that were potentially benefiting. In the meantime, this study will make sure that no one takes antibiotics without need,” said researcher Imre Noth, MD, the chief of UVA Health’s Division of Pulmonary and Critical Care Medicine. “We did view the study as great success as an NIH [National Institutes of Health] initiative, in that the pragmatic design, without blinding patients to treatment, led to rapid enrollment, ahead of schedule and basically ahead of budget, showing that large studies can be accomplished in this uncommon disease.”

About Idiopathic Pulmonary Fibrosis

In idiopathic pulmonary fibrosis, scar tissue builds up in the lungs over time, preventing them from supplying adequate oxygen to the body. It typically affects people over age 50, mostly men. Patients typically survive only two to five years after diagnosis, though some live much longer.

Doctors are uncertain what triggers idiopathic pulmonary fibrosis. (“Idiopathic” means “unknown cause.”) However, environmental and genetic factors may play a part, as may lung infections.

Doctors also suspect that changes in the microorganisms that naturally live in our lungs may be a factor. Scientists have increasingly come to appreciate the importance of the tiny organisms that live in our bodies and on our skin. In idiopathic pulmonary fibrosis, the thinking goes, the natural state of the microorganisms in the lungs may become unbalanced – perhaps there are too many of one type or a general loss of variety. Lab work in mice has suggested that antimicrobials may be able to help fix the problem.

To see if antimicrobial treatments could benefit idiopathic pulmonary fibrosis, researchers at 35 sites around the country conducted a randomized clinical trial with volunteers age 40 or older. A total of 513 patients enrolled between August 2017 and June 2019. Half received antimicrobial drugs, choosing between co-trimoxazol or doxycycline, while the other half received the standard care.

After a median follow-up time of 12.7 months, there was no statistically significant benefit from the antimicrobials. The time to both breathing-related hospitalization or death was unchanged.

The findings echoed those of a previous study, and the researchers say the results show that treatment with antibiotics is ineffective and unwarranted as a general treatment for idiopathic pulmonary fibrosis. They do not rule out, however, that it may be useful in a limited number of patients with known disruptions to their lung microorganisms.

“As the largest single study in IPF ever conducted, I think we are going to learn a lot as we look at things more closely. Might our choice of antibiotics have been the right ones? Were there some patients that did better than others? Who should we be targeting for treatment? All things this study will help in the future,” said Noth, a top expert on the disease. “I am heartened and hopeful moving forward as this study teaches us a lot for the next one, and each study gets us closer to better treatments and a cure.”

Findings Published

The researchers have published their findings in the Journal of the American Medical Association. The research team consisted of Fernando J. Martinez, Eric Yow, Kevin R. Flaherty, Laurie D. Snyder, Michael T. Durheim, Stephen R. Wisniewski, Frank C. Sciurba, Ganesh Raghu, Maria M. Brooks, Dong-Yun Kim, Daniel F. Dilling, Gerard J. Criner, Hyun Kim, Elizabeth A. Belloli, Anoop M. Nambiar, Mary Beth Scholand, Kevin J. Anstrom and Noth for the CleanUP-IPF Investigators of the Pulmonary Trials Cooperative.

The research was supported by the National Institutes of Health’s National Heart, Lung and Blood Institute, grant U01HL128964; Three Lakes Foundation; IPF Foundation; and Veracyte Inc. Noth has received funding from NIH, Veracyte and Three Lakes; personal fees from Boerhinger Ingelheim, Genentech and Confo; and has filed for a patent related to idiopathic pulmonary fibrosis. A full list of the authors’ disclosures is included in the paper.

Featured image: Imre Noth, MD, the chief of UVA Health’s Division of Pulmonary and Critical Care Medicine, says the large study of idiopathic pulmonary fibrosis will still benefit efforts to battle the lung-scarring disease. © UVA Health

Provided by UVA Health

Can Antibiotics Treat Human Diseases in Addition to Bacterial Infections? (Medicine)

According to researchers at the University of Illinois Chicago, the antibiotics used to treat common bacterial infections, like pneumonia and sinusitis, may also be used to treat human diseases, like cancer. Theoretically, at least.

As outlined in a new Nature Communications study, the UIC College of Pharmacy team has shown in laboratory experiments that eukaryotic ribosomes can be modified to respond to antibiotics in the same way that prokaryotic ribosomes do.

Fungi, plants, and animals — like humans — are eukaryotes; they are made up of cells that have a clearly defined nucleus. Bacteria, on the other hand, are prokaryotes. They are made up of cells, which do not have a nucleus and have a different structure, size and properties. The ribosomes of eukaryotic and procaryotic cells, which are responsible for the protein synthesis needed for cell growth and reproduction, are also different.

“Some antibiotics, used for treating bacterial infections, work in an interesting way. They bind to the ribosome of bacterial cells and very selectively inhibit protein synthesis. Some proteins are allowed to be made, but others are not,” said Alexander Mankin, the Alexander Neyfakh Professor of Medicinal Chemistry and Pharmacognosy at the UIC College of Pharmacy and senior author of the study. “Without these proteins being made, bacteria die.”

When people use antibiotics to treat an infection, the cells of the patient are not affected because the drugs are not designed to bind to the differently shaped ribosomes of eukaryotic cells.

“Because there are many human diseases caused by the expression of unwanted proteins — this is common in many types of cancer or neurodegenerative diseases, for example — we wanted to know if it would be possible to use an antibiotic to stop a human cell from making the unwanted proteins, and only the unwanted proteins,” Mankin said.

To answer this question, Mankin and study first author Maxim Svetlov, research assistant professor with the department of pharmaceutical sciences, looked to yeast, a eukaryote with cells similar to human cells.

The research team, which included partners from Germany and Switzerland, performed a “cool trick,” Mankin said. “We engineered the yeast ribosome to be more bacteria-like.”

Alexander Mankin
Alexander Mankin © UIC
Maxim Svetlov
Maxim Svetlov © UIC

Mankin and Svetlov’s team used biochemistry and fine genetics to change one nucleotide of more than 7,000 in yeast ribosomal RNA, which was enough to make a macrolide antibiotic — a common class of antibiotics that works by binding to bacterial ribosomes — act on the yeast ribosome. Using this yeast model, the researchers applied genomic profiling and high-resolution structural analysis to understand how every protein in the cell is synthesized and how the macrolide interacts with the yeast ribosome.

“Through this analysis, we understood that depending on a protein’s specific genetic signature — the presence of a ‘good’ or ‘bad’ sequence — the macrolide can stop its production on the eukaryotic ribosome or not,” Mankin said. “This showed us, conceptually, that antibiotics can be used to selectively inhibit protein synthesis in human cells and used to treat human disorders caused by ‘bad’ proteins.”

The experiments of the UIC researchers provide a staging ground for further studies. “Now that we know the concepts work, we can look for antibiotics that are capable of binding in the unmodified eukaryotic ribosomes and optimize them to inhibit only those proteins that are bad for a human,” Mankin said.

Additional co-authors of the study are Dorota Klepacki and Nora Vázquez-Laslop of UIC; Timm Koller and Daniel Wilson of the University of Hamburg; Sezen Meydan and Nicholas Guydosh of the National Institutes of Health; and Norbert Polacek and Vaishnavi Shankar of the University of Bern.

This work was supported by grants from the National Institutes of Health (R35 GM127134, DK075132, 1FI2GM137845), the German Research Foundation (WI3285/6-1), and the Swiss National Science Foundation (31003A_166527).

Featured image: An antibiotic (green), bound in the human-like yeast ribosome (gray), allows for synthesis of some proteins (represented in orange, purple, and blue) but not others (dark green). (Illustration: Maxim Svetlov/UIC)

Reference: Svetlov, M.S., Koller, T.O., Meydan, S. et al. Context-specific action of macrolide antibiotics on the eukaryotic ribosome. Nat Commun 12, 2803 (2021). https://doi.org/10.1038/s41467-021-23068-1

Provided by UIC

Newer Class of Fluoroquinolone Antibiotics May Present Reduced Risk of Tendon Ruptures (Medicine)

Association between third-generation fluoroquinolones and achilles tendon rupture: A self-controlled case series analysis

It’s widely understood that people taking a common class of antibiotics, like ciprofloxacin and levofloxacin, run the risk of tendonitis and tendon ruptures. However, a new analysis sheds light on newer, third-generation fluoroquinolones and suggests they may have a lower risk of Achilles tendon rupture.

Researchers from Jichi Medical University in Tochigi, Japan, used health care administrative data to identify 504 patient cases of Achilles tendon ruptures with co-occurrence of antibiotics. They found that third-generation fluoroquinolones were not associated with an increase in Achilles tendon rupture.

First- and second-generation fluoroquinolones, like ciprofloxacin and ofloxacin, were at elevated risk of tendon rupture, which was consistent with previous evidence. Third-generation fluoroquinolones include moxifloxacin, garenoxacin, sitafloxacin, prulifloxacin and pazufloxacin, some of which are not yet approved by the Food and Drug Administration in the United States.

The authors note that further studies are required to determine the risks of third-generation fluoroquinolones for other rare adverse events, such as heart damage.

Reference: Takashi Chinen, Yusuke Sasabuchi, Hiroki Matsui and Hideo Yasunaga, “Association Between Third-Generation Fluoroquinolones and Achilles Tendon Rupture: A Self-Controlled Case Series Analysis”, The Annals of Family Medicine May 2021, 19 (3) 212-216; DOI: https://doi.org/10.1370/afm.2673

Provided by American Academy of Family Physicians

New Antibiotic Clears Multi-drug Resistant Gonorrhea in Mice in Single Dose (Medicine)

A new antibiotic compound clears infection of multi-drug resistant gonorrhea in mice in a single oral dose, according to a new study led by researchers at Penn State and Emory University. The compound targets a molecular pathway found in bacteria but not humans and could lead to new treatments for gonorrhea and infections from other bacteria, such as tuberculosis and MRSA.

The research team, which also includes scientists from the biopharmaceutical company Microbiotix, the Uniformed Services University, and Florida State, published their results in a paper appearing March 19 in the journal Nature Communications.

Gonorrhea infects more than 500 thousand people in the United States each year, and several strains of the bacteria that causes the disease, Neisseria gonorrhoeae, are resistant to multiple antibiotics in use today. For this reason, the Centers for Disease Control and Prevention (CDC) lists multi-drug resistant gonorrhea as one of the five most dangerous urgent threats today.

“Many current antibiotics target the process of translation — when proteins are made based on information in genetic material — within the bacteria,” said Ken Keiler, professor of biochemistry and molecular biology at Penn State and an author of the paper. “Over the last decade, we have been investigating a family of compounds that instead inhibit the trans-translation pathway in bacteria, which bacteria use to fix certain kinds of errors during protein synthesis. In this paper, we provide a proof-of-concept that inhibiting the trans-translation pathway can effectively clear multi-drug resistant gonorrhea in animals.”

The researchers previously identified a promising trans-translation inhibitor that clears gonorrhea infection in lab cultures but is ineffective in animals because the compound breaks down. In this study, members of the research team at Microbiotix strategically altered the compound to identify which portions of its structure were necessary to inhibit the pathway and which could be changed to improve its stability.

“Our iterative optimization campaign evaluated over 500 versions of the compound to assess their potency, toxicity, and other pharmacological properties,” said Zachary Aron, director of chemistry at Microbiotix and an author of the paper. “We determined that the central region of the compound plays a critical role in blocking the trans-translation pathway, however modifications at the periphery could be altered to modulate its pharmacological properties. By altering a functional group to sidestep the primary mechanism of metabolism, we can create versions of the compound that are much more stable in animals.”

Members of the research team at the Uniformed Services University then tested one of these modified compounds, MBX-4132, in mice. Their experiments utilized the gonorrhea strain WHO-X, an extremely virulent pathogen that is resistant to almost all approved antibiotics. A single oral dose of the compound completely cleared the infection in 80% of mice within six days, and the bacterial load in the remaining 20% was dramatically reduced.

“Developing a single dose therapy for gonorrhea is incredibly important,” said Keiler. “In some cases, bacteria can develop resistance to a drug when additional doses are skipped, for example when a patient starts to feel better and stops taking antibiotics. With a single dose therapy, a patient could complete the treatment during a visit to their health provider.”

To better determine how the compound inhibits the trans-translation pathway, members of the research team at Emory University and Florida State University used cryo-electron microscopy (cryo-EM) to produce high-resolution images of the compound as it binds to the bacterial ribosome — the macromolecule where proteins are synthesized.

A new antibiotic compound clears infection of multi-drug resistant gonorrhea in mice in a single oral dose, according to a new study. The compound, MBX-4132, binds to the bacterial ribosome and, in so doing, displaces a region of a protein (bL27, purple) that is critical to the trans-translation pathway in bacteria. IMAGE: DUNHAM LAB, EMORY UNIVERSITY

“A derivative of MBX-4132 binds to a location on the ribosome that is different from all known antibiotic binding sites,” said Christine Dunham, associate professor of biochemistry at Emory University and an author of the paper. “The new drug also displaces a region of a ribosomal protein that we think could be important during the normal process of trans-translation. Because trans-translation only occurs in bacteria and not in humans, we hope that the likelihood of the compound affecting protein synthesis in humans is greatly reduced, a hypothesis strongly supported by the safety and selectivity studies performed by Microbiotix.”

The research team plans to further optimize the compound before pursuing preclinical trials.

“This type of compound is actually a broad-spectrum inhibitor,” said Keiler. “It is effective against most Gram-positive bacteria — including tuberculosis and difficult-to-treat staph infections (MRSA) — and some Gram-negative bacteria and could be a promising candidate for future treatments. In this study, we lay the groundwork for using this type of compound and demonstrate that inhibiting the trans-translation pathway in bacteria is a viable antibiotic strategy.”

In addition to Keiler, Aron and Dunham, the research team includes John Alumasa, Mynthia Cabrera and Divya Hosangadi at Penn State; Matthew Torhan, Jay Barbor, Steven Cardinale, Steven Kwasny, Lucas Morin, Michelle Butler, Timothy Opperman and Terry Bowlin at Microbiotix; Atousa Mehrani and Scott Stagg at Florida State; Eric Hoffer and Pooja Srinivas at Emory University; and Kristie Connolly and Ann Jerse at the Uniformed Services University.

This research was supported by the National Institutes of Health.

Featured image: A new antibiotic compound clears infection of multi-drug resistant gonorrhea in mice in a single oral dose, according to a new study.Image: Alissa Eckert/Centers for Disease Control and Prevention

This science news is confirmed by us from Penn State news

Provided by Penn State

How Bacteria Sleep through Antibiotic Attacks? (Biology)

Bacteria can survive antibiotic treatment even without antibiotic resistance by slowing down their metabolism and going into a type of deep sleep. A research team reveals the changes bacteria undergo to reach this “persister” state. Annelies Zinkernagel, an infectiologist at UZH, is main author of the publication in the scientific journal PNAS.

Resistant bacteria evade the effects of antibiotics by becoming less susceptible, for example by breaking the drugs down. But some bacteria have another survival strategy: they withstand treatment by going into a sleep-like state that enables them to tolerate antibiotics. Once therapy is complete, the bacteria wake up and re-establish the infection. This “persister” state can result in recurrent and difficult-to-treat infections.

A research team from several swiss universities has now gained new insights into this bacterial strategy that could lead to new and effective treatments. Last author of the publication in the journal PNAS* is Annelies Zinkernagel, Professor of infectious diseases at the University of Zurich and University Hospital Zurich.

The research team worked with the bacterium Staphylococcus aureus, which is found on the skin of many people and often causes invasive and difficult-to-treat infections. The researchers took bacteria from an infected patient and cultivated them in Petri dishes. Certain bacterial colonies turned out to be smaller than others. “This tells us that the sample contains persistent bacteria,” says Annelies Zinkernagel. “Unlike other bacteria, persistent bacteria must first ‘awaken’, leading to delayed growth in the nutrient medium.”

Detection and analysis of persistent bacteria in a patient sample are particularly interesting because most of the previous studies on persistent bacteria used bacteria that were cultivated over a prolonged period of time in the laboratory and not taken directly from a patient.

Annelies Zinkernagel was able to show that bacteria can slow down their metabolism under certain situations. (Image: Nicolas Zonvi)

To determine the conditions under which bacteria become persistent, the researchers carried out various stress tests. Stress factors include the presence of human immune cells, antibiotics or an acidic environment, as occurs with abscesses. The researchers discovered that the more extreme the stress conditions, the higher the percentage of persistent bacteria.

Slowed metabolism

Using bacteria recently isolated from patients, the researchers also analysed how persistence mechanisms work. To do this, they looked at the entire set of bacterial proteins, known as the proteome. Their analysis showed that comprehensive molecular reprogramming had taken place and slowed metabolism down in persisters.

However, it did not come to a complete standstill, but the bacteria rather entered a kind of deep sleep. In this way, the bacteria increased their chances of survival in a hostile environment. The researchers also observed that as soon as the environment becomes more hospitable, the persistent bacteria reverse these changes and again become infectious.

“The idea that bacteria do not halt their metabolism but slow it down and change it is not entirely new. However, it is still controversial,” says Zinkernagel. “Our study confirms this idea with great precision.” The current study looked primarily at persistent bacteria. “Previous experiments were based on mixed populations, and the results may thus have been biased by the other bacteria, which are usually in the majority.”

New treatments on the horizon

A better understanding of these mechanisms will contribute to developing new treatments against persistent bacteria. The researchers also showed that vitamin A derivatives that target the cell membrane exhibit promising potential for combating less metabolically active bacteria. Alternatively, says Zinkernagel, “if we succeed in reactivating the growth of these bacteria, they would probably no longer be able to evade the antibiotics.”

The fight against persistent bacteria is also important in the fight against resistance, because recurrent infections must be treated with antibiotics over an extended period. This constant exposure increases the risk of developing antibiotic resistance. The research work was supported by the Swiss National Science Foundation and the clinical research priority programme CRPP – BacVivo – Precision medicine for bacterial infections as well as by the Uniscentia Foundation.

Featured image: Stained staphylococci, imaged through a scanning electron microscope. The bacteria colonise the skin and are usually harmless, but they can also cause serious infections. (Image: istock/Dr Microbe)

Reference: M. Huemer, S.M. Shambat et. al: Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success. PNAS (2021)

Provided by University of Zurich

New Weapon Against Resistant Bacteria (Medicine)

Researchers have developed a new antibiotic that can help in the fight against resistant bacteria, and they hope it will reach the patients.

Every day, people die from simple infections even though they have been treated with antibiotics. This is because more and more bacteria have become resistant to the types of antibiotics that doctors can prescribe.

– It’s a huge societal problem and a crisis that we must solve. For example, by developing new antibiotics that can defeat the resistant bacteria, says professor of chemistry at the Department of Physics, Chemistry and Pharmacy, Poul Nielsen.

Resistant bacteria are not only known from pig farms, where it is becoming increasingly difficult to keep the pigsties disease-free. Hospitals are also experiencing with increasing regularity that, for example, infectious diseases cannot be controlled in patients. Thus, an infection in a surgical wound can become life-threatening even if the operation went well.

Resistance can occur very quickly

According to Poul Nielsen, it is important to be at the forefront of the development because the list of resistant bacteria will only grow, which means that the treatment options will be reduced. It is therefore important to develop alternatives that can be used when the current antibiotics no longer work.

– Resistance can occur very quickly, and then it’s essential that we’re ready, he says.

MRSA-infected wound on a hand.© Gregory Moran, M.D.

Together with his research assistant Christoffer Heidtmann and Janne Kudsk Klitgaard from the Department of Biochemistry and Molecular Biology as well as Clinical Microbiology, he has developed a substance that has the potential to become a new effective antibiotic, and SDU has now taken out a patent for it.

Unlike traditional antibiotics such as penicillin, sulfonamides and tetracyclines, this antibiotic is from the pleuromutilin class.

The substance is developed in a medicinal chemistry project and recently published in the Journal of Medicinal Chemistry.

Out to doctors and patients – how?

The substance fights both resistant enterococcus, streptococcus and staphylococcus bacteria. The substance and the pleuromutilin class do this via a unique mechanism of action, which also causes resistance to develop at a very slow pace.

So far, the substance has been tested on bacteria and human cells. The next step towards becoming an approved drug is animal studies and then clinical studies in humans.

Maybe we should consider this a societal task, rather than a task that will only be solved if it’s financially attractive.

— Poul Nielsen, professor

– If this substance is to reach doctors and patients as a drug, comprehensive and cost-intensive further development efforts are needed, which we can only initiate under the auspices of the university.

– The big pharmaceutical companies have that kind of money, but they are traditionally not interested in this kind of tasks, because they are not financially attractive, says Poul Nielsen.

Should it be a societal task?

According to Poul Nielsen, there are several reasons why it is not financially attractive to develop new antibiotics:

  1. Antibiotics are only taken for days or weeks. There is more money in drugs for chronically ill people, such as antidepressants or blood pressure medicine.
  2. Newly developed antibiotics will be backups and not used until the current antibiotics no longer work. So earnings are not just around the corner.
  3. The bacteria can also become resistant to a new antibiotic, and then it has to be taken off the market again.

– However, this doesn’t change the fact that the world community is in dire need of new effective drugs against antibiotic resistance. Maybe we should consider this a societal task, rather than a task that will only be solved if it’s financially attractive, says Poul Nielsen.

He and his colleagues hope that the work of further developing their new antibiotic can continue. Whether it will happen, and whether it will be in a public or private context, only time will tell.

Featured image: Colorbox

Reference: Heidtmann CV, Voukia F, Hansen LN, Sørensen SH, Urlund B, Nielsen S, Pedersen M, Kelawi N, Andersen BN, Pedersen M, Reinholdt P, Kongsted J, Nielsen CU, Klitgaard JK, Nielsen P. Discovery of a Potent Adenine-Benzyltriazolo-Pleuromutilin Conjugate with Pronounced Antibacterial Activity against MRSA. J Med Chem. 2020 Dec 24;63(24):15693-15708. doi: 10.1021/acs.jmedchem.0c01328. Epub 2020 Dec 16. PMID: 33325700.

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