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Juan Lama
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Antiviral drugs are used globally as treatment and prophylaxis for long-term and acute viral infections. Even though antivirals also have been shown to have off-target effects on bacterial growth, the potential contributions of antivirals to antimicrobial resistance remains unknown. Herein we explored the ability of different classes of antiviral drugs to induce antimicrobial resistance. Our results establish the previously unrecognized capacity of antivirals to broadly alter the phenotypic antimicrobial resistance profiles of both gram-negative and gram-positive bacteria Escherichia coli and Bacillus cereus. Bacteria exposed to antivirals including zidovudine, dolutegravir and raltegravir developed cross-resistance to commonly used antibiotics including trimethoprim, tetracycline, clarithromycin, erythromycin, and amoxicillin. Whole genome sequencing of antiviral-resistant E. coli isolates revealed numerous unique single base pair mutations, as well as multi-base pair insertions and deletions, in genes with known and suspected roles in antimicrobial resistance including those coding for multidrug efflux pumps, carbohydrate transport, and cellular metabolism. The observed phenotypic changes coupled with genotypic results indicate that bacteria exposed to antiviral drugs with antibacterial properties in vitro can develop multiple resistance mutations that confer cross-resistance to antibiotics. Our findings underscore the potential contribution of wide scale usage of antiviral drugs to the development and spread of antimicrobial resistance in humans and the environment. Bacteria exposed to antiviral drugs in vitro can develop multiple resistance mutations that confer cross-resistance to antibiotics. Published (Aug.12, 2023) in Communications Biology: https://doi.org/10.1038/s42003-023-05177-3
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Juan Lama
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For the first time, bacteriophages — viruses that kill bacteria — eliminated an antibiotic-resistant mycobacterial lung infection in a man with advanced cystic fibrosis (CF) lung disease, a study reported. As a result, the patient was able to undergo a successful lung transplant after on. “I am so grateful for the effort, persistence and creativity of all the people who were involved in my treatment,” Jarrod Johnson, the recipient of the lung transplant, said in a press release. “I thought I was going to die. They have literally saved my life.” Added Jerry Nick, MD, study lead and director of the adult CF program at National Jewish Health in Colorado: “This research can serve as a road map for future use of phages to treat patients with severe Mycobacterium abscessus lung infection and to save lives.” The study, “Host and pathogen response to bacteriophage engineered against Mycobacterium abscessus lung infection,” was published in Cell. The buildup of thick mucus in the lungs is a hallmark of CF, which can lead to recurrent and damaging bacterial infections and eventually lung failure, requiring transplant. Mycobacteria are a common type of bacteria that can cause tuberculosis, leprosy, and non-tuberculous mycobacterial (NTM) infections. They can be aggressive and difficult to treat, even with combinations of multiple antibiotics over long periods. Johnson is a 26-year-old man with CF who experienced repeated lung infections throughout childhood and, as a result, was admitted to hospitals several times a year. As an adult, his lung function rapidly declined due to persistent infection by Mycobacterium abscessus, which did not respond to antibiotic treatment. It recently dropped below 30% and he needed a transplant. However, due to the ongoing mycobacteria infection, which had spread to his skin and other tissues, and the lack of effective treatments, he was unable to undergo the procedure. Bacteriophages, or phages, are viruses that selectively target and kill bacteria. There has been a growing interest in using phages to treat antibiotic-resistant bacterial infections in recent years. To date, phages have not been used to treat a mycobacterial infection of the lungs. In this report, Nick and colleagues describe how Johnson’s mycobacteria infection was eradicated by phage therapy, which allowed him to undergo a lung transplant. “We had tried unsuccessfully for years to clear the mycobacterial infection with a variety of antibiotics,” Nick said. “When we used the bacteria’s own natural enemies, we were able to clear the infection which resulted in a successful lung transplant.” Sputum samples were collected from Johnson, M. abscessus was grown in culture, then screened against a panel of phages, which were genetically engineered to improve their bacteria-killing potential. Two specific phages were identified that efficiently killed the bacteria, either alone or in combination, over a wide range of phage and bacterial levels. While he was in the hospital for an acute worsening of his symptoms, the therapeutic phage cocktail was infused into Johnson’s bloodstream twice daily. It was well tolerated, with no reported side effects. He was discharged five days later and continued on two phage treatments a day. Johnson was readmitted to the hospital four times in the year after starting phage therapy because of pulmonary exacerbations. Sputum samples were collected for up to a year, which were largely positive for M. abscessus to day 96 (about three months). However, most of the following cultures were negative for up to one year. At around three months, he began CF treatment with Trikafta. Although his lung function ranged from 23% to 31% over the year following phage therapy, similar to before treatment, his time in the hospital decreased. Based on the absence of M. abscessus infection, he was listed for a lung transplant one year after phage therapy and underwent a successful transplant soon after, in October 2021. Phage therapy continued throughout his recovery for up to 500 days (about 16 months). CT scans of his lung during phage therapy showed some improvements over time, along with markers for M. abscessus death. There was no evidence of resistance to phage therapy. All M. abscessus samples isolated over the course of his infection were tested against 20 antibiotics, most of which were consistently resistant or demonstrated little variability, “suggesting the combination of phage and antibiotics did not result in greater antibiotic resistance,” the researchers wrote. Lastly, because phage treatment can fail due to the emergence of anti-phage antibodies, his blood was collected and tested. Surprisingly, Johnson had a substantial antibody response to both phages even before treatment, suggesting that “this individual had naturally encountered phages,” the researchers noted. Antibody levels increased modestly in post-treatment blood samples, but he did not mount a substantial additional antibody response to one of the phages until late in the treatment regimen. At that point, sputum cultures were primarily negative for M. abscessus. “The use of phages in very advanced lung disease with the objective to sufficiently control M. abscessus as a bridge to lung transplant may be considered based on this report,” the researchers wrote. The Cystic Fibrosis Foundation and the National Institutes of Health provided funding for the treatment and study. Cited research published in Cell (May 13, 2022): https://doi.org/10.1016/j.cell.2022.04.024
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Juan Lama
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NIH preclinical study suggests FDA-approved tetracycline-based antibiotics may slow infection and reduce neurological problems. In 2015, hundreds of children were born with brain deformities resulting from a global outbreak of Zika virus infections. Recently, National Institutes of Health researchers used a variety of advanced drug screening techniques to test out more than 10,000 compounds in search of a cure. To their surprise, they found that the widely used antibiotic methacycline was effective at preventing brain infections and reducing neurological problems associated with the virus in mice. In addition, they found that drugs originally designed to combat Alzheimer’s disease and inflammation may also help fight infections. “Around the world, the Zika outbreak produced devastating, long-term neurological problems for many children and their families. Although the infections are down, the threat remains,” said Avindra Nath, M.D., senior investigator at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and a senior author of the study published in PNAS(link is external). “We hope these promising results are a good first step to preparing the world for combating the next potential outbreak.” The study was a collaboration between scientists on Dr. Nath’s team and researchers in laboratories led by Anton Simeonov, Ph.D., scientific director at the NIH’s National Center for Advancing Translational Sciences (NCATS) and Radhakrishnan Padmanabhan, Ph.D., Professor of Microbiology & Immunology, Georgetown University Medical Center(link is external), Washington, D.C. The Zika virus is primarily spread by the Aedes aegypti mosquito. In 2015 and 2016, at least 60 countries reported infections. Some of these countries also reported a high incidence of infected mothers giving birth to babies born with abnormally small heads resulting from a developmental brain disorder called fetal microcephaly. In some adults, infections were the cause of several neurological disorders including Guillain-Barré syndrome, encephalitis, and myelitis. Although many scientists have tried, they have yet to discover an effective treatment or vaccination against the virus. In this study, the researchers looked for drugs that prevent the virus from reproducing by blocking the activity of a protein called NS2B-NS3 Zika virus protease. The Zika virus is a protein capsule that carries long strings of RNA-encoded instructions for manufacturing more viral proteins. During an infection, the virus injects the RNA into a cell, resulting in the production of these proteins, which are strung together, side-by-side, like the parts in a plastic model airplane kit. The NS2B-NS3 protease then snaps off each protein, all of which are critical for assembling new viral particles. “Proteases act like scissors. Blocking protease activity is an effective strategy for counteracting many viruses,” said Rachel Abrams, Ph.D., an organic chemist in Dr. Nath’s lab and the study leader. “We wanted to look as far and wide as possible for drugs that could prevent the protease from snipping the Zika virus polyprotein into its active pieces.” To find candidates, Dr. Abrams worked with scientists on Dr. Simeonov’s and Dr. Padmanabhan’s teams to create assays, or tests, for assessing the ability of drugs to block NS2B-NS3 Zika virus protease activity in plates containing hundreds of tiny test tubes. Each assay was tailored to a different screening, or sifting, technique. They then used these assays to simultaneously try out thousands of candidates stored in three separate libraries. One preliminary screen of 2,000 compounds suggested that commonly used, tetracycline-based antibiotic drugs, like methacycline, may be effective at blocking the protease. Meanwhile, a large-scale screen of more than 10,000 compounds helped identify an investigational anti-inflammatory medicine, called MK-591, and a failed anti-Alzheimer’s disease drug, called JNJ-404 as potential candidates. A virtual screen of over 130,000 compounds was also used to help spot candidates. For this, the researchers fed the other screening results into a computer and then used artificial intelligence-based programs to learn what makes a compound good at blocking NS2B-NS3 Zika virus protease activity. “These results show that taking advantage of the latest technological advances can help researchers find treatments that can be repurposed to fight other diseases,” said Dr. Simeonov. The Zika virus is known to preferentially infect stem cells in the brain. Scientists suspect this is the reason why infections cause more harm to newborn babies than to adults. Experiments on neural stem cells grown in petri dishes indicated that all three drugs identified in this study may counteract these problems. Treating the cells with methacycline, MK-591, or JNJ-404 reduced Zika virus infections. Because tetracyclines are U.S. Food and Drug Administration-approved drugs that are known to cross the placenta of pregnant women, the researchers focused on methacycline and found that it may reduce some neurodevelopmental problems caused by the Zika virus. For instance, Zika-infected newborn mice that were treated with methacycline had better balance and could turn over more easily than ones that were given a placebo. Brain examinations suggested this was because the antibiotic reduced infections and neural damage. Nevertheless, the antibiotics did not completely counteract harm caused by the Zika virus. The weight of mice infected with the virus was lower than control mice regardless of whether the mice were treated with methacycline. “These results suggest that tetracycline-based antibiotics may at least be effective at preventing the neurological problems associated with Zika virus infections,” said Dr. Abrams. “Given that they are widely used, we hope that we can rapidly test their potential in clinical trials. Findings published in PNAS (Nov. 23, 2020): https://doi.org/10.1073/pnas.2005463117
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Juan Lama
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A laboratory study unravels ways non-antibiotic drugs can contribute to drug resistance. The emergence of disease-causing bacteria that are resistant to antibiotics is often attributed to the overuse of antibiotics in people and livestock. But researchers have homed in on another potential driver of resistance: antidepressants. By studying bacteria grown in the laboratory, a team has now tracked how antidepressants can trigger drug resistance. “Even after a few days exposure, bacteria develop drug resistance, not only against one but multiple antibiotics,” says senior author Jianhua Guo, who works at the Australian Centre for Water and Environmental Biotechnology at the University of Queensland in Brisbane. This is both interesting and scary, he says. Globally, antibiotic resistance is a significant public-health threat. An estimated 1.2 million people died as a direct result of it in 20192, and that number is predicted to climb. Early clues Guo became interested in the possible contributions of non-antibiotic drugs to antibiotic resistance in 2014, after work by his lab found more antibiotic-resistance genes circulating in domestic wastewater samples than in samples of wastewater from hospitals, where antibiotic use is higher. Guo’s group and other teams also observed that antidepressants — which are among the most widely prescribed medicines in the world — killed or stunted the growth of certain bacteria. They provoke “an SOS response”, Guo explains, triggering cellular defence mechanisms that, in turn, make the bacteria better able to survive subsequent antibiotic treatment. In a 2018 paper, the group reported that Escherichia coli became resistant to multiple antibiotics after being exposed to fluoxetine, which is commonly sold as Prozac. The latest study examined 5 other antidepressants and 13 antibiotics from 6 classes of such drugs and investigated how resistance in E. coli developed. In bacteria grown in well-oxygenated laboratory conditions, the antidepressants caused the cells to generate reactive oxygen species: toxic molecules that activated the microbe’s defence mechanisms. Most prominently, this activated the bacteria’s efflux pump systems, a general expulsion system that many bacteria use to eliminate various molecules, including antibiotics. This probably explains how the bacteria could withstand the antibiotics without having specific resistance genes. But exposure of E. coli to antidepressants also led to an increase in the microbe’s mutation rate, and the subsequent selection of various resistance genes. However, in bacteria grown in anaerobic conditions, levels of reactive oxygen species were much lower and antibiotic resistance developed much more slowly. Moreover, at least one antidepressant, sertraline, promoted the transfer of genes between bacterial cells, a process that can speed up the spread of resistance through a population. Such transfer can occur between different types of bacterium, allowing resistance to hop between species — including from harmless bacteria to pathogenic ones. Growing recognition Kiran Patil, who studies microbiome–chemical interactions at the University of Cambridge, UK, says that in the past five years there has been a growing appreciation that many non-antibiotic medicines that target human cells can also affect bacteria and contribute to antibiotic resistance. “The strength of the study is the mechanistic details,” says Patil. Lisa Maier, who is based at the University of Tübingen in Germany and studies interactions between drugs and the microbiome, says that to understand how antidepressants can drive antibiotic resistance, researchers need to determine what molecules the drugs are targeting in the bacteria and to assess the effects of the medications on a wider variety of clinically relevant bacterial species. In 2018, Maier and her colleagues surveyed 835 medicines that did not target microbes and found that 24% inhibited the growth of at least one strain of human gut bacteria. Patil and Maier say it is important to gather evidence to assess the real-world impact of antidepressants on resistance, such as whether antidepressants are driving the accumulation of antibiotic-resistant bacteria, particularly disease-causing ones, in people, animals or the environment. Although significant amounts of antidepressants have been found in wastewater, reported levels tend to fall below the concentrations at which Guo’s group saw significant effects in E. coli. But concentrations of some of the antidepressants that had strong effects in this study are expected to be reached in the large intestines of people taking the drugs. Follow-up studies Maier says that several studies now link antidepressants and other non-antibiotic pharmaceuticals to changes in bacteria, and that preliminary studies have given the “first hints” regarding how such drugs can affect the microbiomes of people taking them. But in healthy humans, E. coli is found mainly in the large intestine, where conditions are anaerobic, meaning that the process described in the paper might not occur at the same rate in people, says Maier. Future studies should use bacterial growing conditions that model sites at which antidepressants might be acting, says Patil. Guo says his lab is now looking at the microbiomes of mice given antidepressants. Early, unpublished data suggest that the drugs can change the animals’ gut microbiota and promote gene transfer. But Guo and Maier caution people against stopping taking antidepressants on the basis of this research. “If you have depression, that needs to be treated in the best possible way. Then, bacteria second,” says Maier. Researchers and pharmaceutical companies need to quantify the contribution of non-antibiotic pharmaceuticals to antibiotic resistance, says Guo. “Non-antibiotic pharmaceuticals are a big concern that we shouldn’t overlook,” he says. Published in Nature (Jan. 24, 2023): https://doi.org/10.1038/d41586-023-00186-y
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Juan Lama
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The National Institute of Allergy and Infectious Diseases awarded $2.5 million in grants to 12 institutions to study using bacteriophage therapy to combat antimicrobial-resistant bacteria. Bacteriophages, or phages, are viruses that target and consume bacteria. They are being used in some cases as a last resort to treat resistant bacterial infections that have not responded to traditional antibiotics. “In recent decades, multidrug-resistant bacteria, particularly those that cause potentially deadly diseases like tuberculosis, have become a serious and growing global public health concern,” NIAID Director Anthony S. Fauci, MD, said in a press release. “With these awards, NIAID is supporting research needed to determine if phage therapy might be used in combination with antibiotics — or replace them altogether — in treating evolving antibiotic-resistant bacterial diseases.” The NIH said the funding will address knowledge gaps related to phages, including a study characterizing various types of phages, research investigating how phages combat biofilms, and research to determine how to identify new phages. Grant recipients include researchers from the Albert Einstein College of Medicine, University of Alabama at Birmingham, University of Connecticut, Georgia Institute of Technology, Harvard School of Public Health, University of Pittsburgh, Queens College, Texas A&M Agrilife Research, University of Wisconsin-Madison, Geneve Foundation, Guild Associates, and PhagePro.
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