Resistance to antibiotics is a problem that alarms the medical and scientific community. Bacteria resistant to three different classes of antibiotics, known as multi-drug resistant (MDR) bacteria, are far from rare. Some are even resistant to all currently available treatments and are known as pan-drug resistant (PDR). They are associated with dangerous infections and listed by the World Health Organization (WHO) as priority pathogens for drug development with maximum urgency.
An article published in a special issue of the journal Antibiotics highlights a compound with antibacterial activity that presented promising results within one hour in laboratory trials.
The study was led by Ilana Camargo, last author of the article, and conducted during the doctoral research of first author Gabriela Righetto at the Molecular Epidemiology and Microbiology Laboratory (LEMiMo) of the University of São Paulo’s São Carlos Institute of Physics (IFSC-USP) in Brazil.
The compound we discovered is a new peptide, Pln149-PEP20, with a molecular framework designed to enhance its antimicrobial activity and with low toxicity. The results can be considered promising insofar as the trials involved pathogenic bacteria associated with MDR infections worldwide.”
Adriano Andricopulo, co-author of the article
Although novel antibacterial drugs are urgently needed, the pharmaceutical industry is notoriously uninterested in pursuing them, mainly because research in this field is time-consuming and costly, requiring very long lead times to bring viable active compounds to market.
The Center for Innovation in Biodiversity and Drug Discovery (CIBFar), a Research, Innovation and Dissemination Center (RIDC) set up and funded by FAPESP, looks for molecules that can be used to combat multidrug-resistant bacteria.
Camargo and Andricopulo are researchers at CIBFar, as are two other co-authors who study promising bactericidal compounds: Leila Beltramini and José Luiz Lopes.
For over a decade, the group formed by the collaboration between Beltramini and Lopes has analyzed Plantaricin 149 and its analogs. Plantaricins are substances produced by the bacterium Lactobacillus plantarum to combat other bacteria.
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Lactobacillus plantarum is commonly found in nature, especially in anaerobic plant matter, and in many fermented vegetable, meat and dairy products.
In the case of Plantaricin 149, Japanese researchers were the first to report its bactericidal action (in 1994) and since then scientists have been interested in obtaining more efficient synthetic analogs (molecules with small structural differences). In 2007, one of the first projects completed by the CIBFar team showed that the peptide inhibits pathogenic bacteria such as Listeria spp. and Staphylococcus spp. They then began studying synthetic analogs with stronger bactericidal activity than the original (causing more damage to the membrane of the combated microorganisms).
With the support of a scholarship from FAPESP, Righetto synthesized 20 analogs of Plantaricin 149, finding that Pln149-PEP20 had the best results so far and was also half the size of the original peptide. “The main advances in our research consist of the development of this smaller, more active and less toxic molecule, and the characterization of its action and propensity to develop resistance. It has proven to be highly promising in vitro – active against MDR bacteria and extensively resistant bacteria,” said Camargo, principal investigator for the project.
LEMiMo, the laboratory where the studies were conducted, has experience in characterizing bacterial isolates involved in outbreaks of hospital infections and holds a collection of bacteria selected for these trials in search of novel active compounds. The bacteria have the resistance profiles currently of greatest concern and were isolated during hospital outbreaks.
They are known in the scientific community by the term ESKAPE, an acronym for the scientific names of six highly virulent and antibiotic-resistant bacterial pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.
Further research can now be conducted to investigate the molecule’s action mechanism in more depth, to look for formulations, and possibly to develop an application. “In terms of the action mechanism, it’s also possible to use the cell morphology of the bacteria to identify cellular pathways affected by the peptide,” Righetto said. “As for optimization, the molecule can be functionalized by being linked to macrostructures, and the amino acid sequence can be modified.” Research is also needed on its cytotoxicity and on its selectivity (whether it affects healthy cells).
“We’re living in times of major global public health hazards due to a lack of antimicrobials that can be used to treat infections caused by extremely resistant bacteria. Antimicrobial peptides are targets of great interest for the development of novel candidate drugs. This novel molecule has the potential to be used as an innovative antimicrobial therapy, but further modifications and molecular optimizations still need to be investigated,” Andricopulo said.
Publication of the article also involved Harvard Medical School’s Infectious Disease Institute in Boston (USA) via researchers Paulo José Martins Bispo and Camille André.
Righetto, G. M., et al. (2023). Antimicrobial Activity of an Fmoc-Plantaricin 149 Derivative Peptide against Multidrug-Resistant Bacteria. doi.org/10.3390/antibiotics12020391.
Increases in multidrug-resistance in the bacteria Streptococcus pneumoniae have made it the fourth-leading cause of death associated with antibiotic resistance.
In a study in PLOS Biology, researchers report a new target to fight against pneumonia due to infections by this opportunistic lung pathogen -; interference with the bacteria’s fermentation metabolism. This may offer a novel therapeutic option in the urgent need to discover new strategies to combat drug-resistant S. pneumoniae.
In a proof of principle, University of Alabama at Birmingham researchers showed that giving an existing drug -; one already approved by the United States Food and Drug Administration to treat methanol poisoning – in combination with the antibiotic erythromycin significantly reduced disease in mice infected with a virulent, multidrug-resistant S. pneumoniae. The combination therapy reduced bacterial burden in the lungs by 95 percent, and bacterial burdens in the spleen and heart by 100- and 700-fold, respectively. The FDA-approved drug alone, or erythromycin alone, had no effect.
Fomepizole, the FDA-approved drug, disrupts activity of the enzyme alcohol dehydrogenase in the bacteria. The mice were infected intratracheally with the multidrug-resistant clinical isolate S. pneumoniae serotype 35B strain 162–5678, which has high resistance to erythromycin. Notably, the S. pneumoniae 35B serotype has been reported as an emerging multidrug-resistant serotype in clinical settings. Eighteen hours after infection, the mice were given a single injection of erythromycin, with or without fomepizole.
Fomepizole, or other drugs that inhibit bacterial metabolism, have potential to dramatically increase the efficacy of erythromycin and other antibiotics, respectively, in vivo.”
Carlos Orihuela, Ph.D., professor and interim chair of the UAB Department of Microbiology
A broad foundation of basic research preceded this proof-of-principle experiment.
S. pneumoniae relies on fermentation and glycolysis to produce energy. During fermentation, pyruvate is converted to lactate, acetate and ethanol, and NADH is oxidized to regenerate NAD+, which is needed for glycolysis. Accordingly, maintenance of an available NAD+ pool, necessary for redox balance, is vital for sustained energy production, bacterial growth and survival.
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Orihuela and UAB colleagues made S. pneumoniae mutants in five enzymes involved in fermentation and NAD+ production, and they found, in general, that the mutants had impaired metabolism. Two of the mutants, one for lactate dehydrogenase and one for alcohol dehydrogenase, had stark decreases in intracellular pool of ATP, the energy molecule of living cells. The other three mutants had significant, but more modest, decreases.
NAD+/NADH redox imbalances in the mutants generally interfered with production of S. pneumoniae virulence factors and colonization in the mouse nasopharynx. Some of the mutations influenced susceptibility to antibiotics, as tested with three antibiotics, including erythromycin, that interfere with protein synthesis, two antibiotics that disrupt cell wall synthesis and one antibiotic that targets DNA transcription.
Researchers found that treating a wildtype S. pneumoniae, which did not have mutations in alcohol dehydrogenase or the other enzymes, with fomepizole alone caused redox imbalances. In vitro tests showed that treatment of S. pneumoniae with fomepizole enhanced the susceptibility to antibiotics, including fourfold decreases in the minimal inhibitory concentrations of the antibiotics erythromycin and gentamicin.
“We also evaluated whether fomepizole treatment impacted the antibiotic susceptibility of other anaerobic gram-positive bacteria, including other streptococcal pathogens, including Streptococcus pyogenes, Streptococcus agalactiae and Enterococcus faecium, to erythromycin or gentamicin,” Orihuela said. “We observed from twofold to eightfold decreased minimal inhibitory concentration with fomepizole in most cases, including E. faecium.”
“Our results indicate that the blocking of NAD+ regeneration pathways during infection is a way to increase antibiotic susceptibility in drug-resistant gram-positive anaerobic pathogens,” Orihuela said. “This has clinical potential with regard to microbial eradication and treatment of disseminated infection.”
Globally, more than 3 million individuals are hospitalized due to pneumococcal disease annually, and hundreds of thousands die as a result.
In a recent study published in Microbiology Spectrum, researchers found that differences in the dietary patterns of children with normal weight and those who were overweight or obese contributed to variations in the gut microbiome diversity, virulence factors of gut bacteria, and metabolic function.
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A growing body of evidence indicates that gut microbiota has a significant role in various aspects of host metabolism, including digestion, harvesting of energy, and induction of low-grade inflammation. In addition, the genetic factors of the host, as well as other characteristics such as age, diet, immunity, and gender, influence the gut microbiome composition.
Research shows that bacterial diversity in the gut and the individual’s functional capacity vary between those with normal weight and obese individuals. Gut microbiome profile variations have also been linked to metabolic disorders, lipid accumulation, and inflammation.
Lipogenesis in the liver and the regulation of appetite through hormones are also associated with gut microbiome genes.
Aside from its role in adipogenesis, superoxide reduction, and the metabolism of vitamins, gut microbiota also regulates innate immunity and the systemic, low-grade inflammatory state that can contribute to fat deposition and obesity. Therefore, Dysbiosis, which is the imbalance of gut microbiota, combined with diet, likely has a significant role in the development of obesity.
About the study
In the present study, researchers conducted a cross-sectional analysis of data from 45 children between the ages of six and 12 to determine the association between gut microbiota and obesity.
Questionnaires were used to obtain information on dietary frequencies, gender, age, and body mass index (BMI). Based on the World Health Organization (WHO) z-scores, in which BMI is adjusted for gender and age, the children were classified into two categories of overweight and obese (OWOB) and normal weight (NW).
Data from food frequency questionnaires were used to classify the dietary habits of children into two nutritional patterns. To this end, Pattern 1 was characterized by complex carbohydrates and proteins, whereas Pattern 2 comprised simple carbohydrates and saturated fats.
Shotgun metagenomics was used to assess the taxonomic diversity of the gut microbiota and metabolic capacity from genomic deoxyribonucleic acid (DNA) extracted from fecal samples. Clade-specific markers were used for the taxonomic and functional assessment of the gut bacteria. Additionally, reverse Simpson and Shannon diversity indices were calculated.
The virulence factor database was used to screen for virulence factor genes, whereas multivariate linear modeling was used to determine the association between the taxa, virulence factors, and function of gut microbes and covariates of diet, serology, and anthropometric measurements.
Study findings
Significant differences between the alpha and beta diversity of the gut microbiota were observed between the children in the NW and OWOB groups, thus suggesting that specific phyla of bacteria contribute to higher levels of energy harvest.
Furthermore, species such as Ruminococcus species, Victivallis vadensis, Mitsuokella multacida, Alistipes species, Clostridium species, and Acinetobacter johnsonii were linked to healthier metabolic parameters.
In contrast, an increase in the abundance of bacteria such as Veillonellaceae, Lactococcus, Fusicatenibacter saccharivorans, Fusicatenibacter prausnitzii, Eubacterium, Roseburia, Dialister, Coprococcus catus, Bifidobacterium, and Bilophila was identified in children with pro-inflammatory conditions and obesity.
Bacteria such as Citrobacter europaeus, Citrobacter youngae, Klebsiella variicola, Enterococcus mundtii, Gemella morbillorum, and Citrobacter portucalensis were associated with higher lipid and sugar intake, as well as higher blood biochemistry values and anthropometric measurements.
Diets high in fats and simple carbohydrates have been associated with the abundance of Citrobacter and Klebsiella species in the gut. Moreover, previous studies have indicated that these bacterial species are potential markers of inflammation, obesity, and an increase in fasting glucose.
The metabolism of menaquinones and gamma-glutamyl was negatively associated with BMI. Furthermore, the microbiomes of children in the NW group preserved a more consistent alpha diversity of virulence factors, while OWOB microbiomes exhibited a dominance of virulence factors.
Differences in the metabolic capacities pertaining to biosynthesis pathways of vitamins, carriers, amino acids, nucleotides, nucleosides, amines, and polyamines, as well as the degradation of nucleotides, nucleosides, and carbohydrate-sugars, were also found between the NW and OWOB groups.
Conclusions
Dietary profiles and the diversity of gut microbiota were found to be interconnected and associated with changes in metabolic parameters, the dominance of virulence factors, and obesity. Changes in gut microbiome diversity and relative abundance have been linked to obesity, inflammatory responses, and metabolic disorders.
Taken together, the study findings suggested that the prevalence of virulence factors, as well as the metabolic and genetic roles of gut microbiota in increasing inflammation, can help identify individuals at an increased risk of childhood obesity.
Journal reference:
Murga-Garrido, S. M., Ulloa-Pérez, E. J., Díaz-Benítez, C. E., et al. (2023). Virulence factors of the gut microbiome are associated with BMI and metabolic blood parameters in children with obesity. Microbiology Spectrum. doi:10.1128/spectrum.03382-22
Thought LeadersDr. Tomislav MeštrovićAffiliate Associate ProfessorUniversity of WashingtonAs part of World Antimicrobial Resistance Week 2022, News-Medical speaks to Dr. Tomislav Meštrović about his new research discussing the burden of bacterial antimicrobial resistance in the WHO European region, as well as about how we can prevent antimicrobial resistance together.
Please can you introduce yourself and tell us about your background and interest in antimicrobial resistance (AMR)?
Before participating in the research on the global burden of antimicrobial resistance (AMR), as a medical doctor, clinical microbiologist, and biomedical scientist, I was a part of relevant research endeavors on antibiotic resistance in my home country Croatia – such as a nationwide study on extended-spectrum beta-lactamases and plasmid diversity in urinary Escherichia coli isolates, as well as describing the emergence of multidrug-resistant Proteus mirabilis in long-term care facilities.
Since my Ph.D. thesis was on addressing AMR in the most common sexually transmitted bacterial agent, Chlamydia trachomatis, I was also a part of the team that aimed to standardize the method for laboratory susceptibility testing of chlamydiae by using both special cell culture and direct molecular-based monitoring, which was published in one methodological textbook.
Therefore, I would say AMR in different microorganisms was always my passion – from the diagnostic standpoint and the therapeutic one. More specifically, I was also involved in certain aspects of drug research, such as proposing a novel dual antagonist to prevent and treat urinary Escherichia coli infections and the usage of liposomal encapsulation to increase the efficacy of azithromycin against Chlamydia trachomatis. The latter technology gained a lot of prominence when liposome-based mRNA COVID-19 vaccines entered the market, so it is no wonder that we tried to capitalize on the positive aspects of such an approach.
Regarding my other professional positions, I am also a Secretary General of the Croatian Society for Clinical Microbiology, Executive Committee Member of the ESCMID study group for Mycoplasma and Chlamydia Infections, and External Affairs Committee Member of the Society for Healthcare Epidemiology of America (SHEA). I have several leadership roles in the American Society for Microbiology (ASM), where I organized conference sessions on antibiotic resistance, such as the Track Hub Session for ASM Microbe, “The global scenario of antimicrobial resistance: do developing and developed countries share the same threats?”. Finally, I am very invested in science communication. As one of the writers for News-Medical, I have written several pieces on the topic of antimicrobial resistance and many other topics.
AMR is a threat to not only humans but also animals, plants, and the environment. Can you tell us more about what exactly AMR is?
Antimicrobial resistance (AMR) is regarded as one of the predominant and most salient public health issues of the 21st century, as it threatens the effective treatment and prevention of an ever-growing range of infections caused by bacteria, viruses, fungi, and parasites. In other words, these groups of microorganisms are no longer susceptible to the common medical agents used to treat them, and the issue is particularly serious and urgent in bacteria. This is an evolving issue that took place over several decades, resulting in frequent pathogenic bacteria harboring some type of resistance to each new antibiotic coming to the market. This means there is an urgent call for action to avoid a global crisis in health care when we can lose the ability to perform surgeries and other types of quotidian medical procedures.
In an attempt to define AMR, we can say that this is a natural phenomenon arising when microorganisms are exposed to antimicrobials or antibiotics. Under such selective pressure, susceptible bacteria are inhibited or killed, whereas those that are naturally (or intrinsically) resistant or those with antibiotic-resistant traits have a much greater chance of surviving and multiplying. The issue arises not only as a result of the overuse of antimicrobial agents but also when they are used inappropriately (such as inadequate drug choices, faulty dosing regimens, and/or low compliance to relevant treatment guidelines). All of this can have a compounding effect and contribute to the rise of antibiotic resistance.
During the last few years, the importance of animal reservoirs and the environment in spreading AMR has been widely recognized. In the past several decades, we have witnessed an increased awareness of the potential problems that resistance among food-producing animals could have on human health. In addition, the soil is regarded as a reservoir of AMR genes since most antibiotics are derived from soil microorganisms that are intrinsically resistant to the antibiotics produced. Finally, water potentially contaminated with organic fertilizers and fecal microorganisms may disseminate resistant bacteria in the soil and is considered a principal way of bacterial propagation between various environmental compartments.
Given the dangers of AMR and the slogan of World Antimicrobial Awareness Week – ‘Antimicrobials: Handle with Care,’ why is it crucial to handle antimicrobials with care?
Judicious and careful use of antimicrobial agents is one of the pillars of successfully diminishing the threat of AMR. In the clinical milieu, there is an important concept of antimicrobial stewardship that refers to a set of coordinated strategies for improving patient care and outcomes by instituting optimal therapy, minimizing collateral damage by reducing antimicrobial usage (which translates to lower resistance rates), and lowering the price of antimicrobials. This concept is also amenable to global implementation to help control AMR by increasing awareness of the public and educating healthcare professionals on the prudent use of antimicrobials.
In the hospital setting, antimicrobial stewardship programs and infection control measures are of utmost importance to prevent the emergence and transmission of antibiotic-resistance microorganisms and preserve the effectiveness of currently available antimicrobial drugs. Hence, multidisciplinary teams of experts (such as infectious disease specialists, medical microbiologists, and clinical pharmacists) participate in such endeavors. Moreover, as the ongoing COVID-19 pandemic can lead to the increased indiscriminate usage of antimicrobials (which was particularly the case in the early days of SARS-CoV-2 spread), handling antibiotics with care can result in lower bacterial resistance and, subsequently, a lower death toll.
Nevertheless, the antimicrobial stewardship concept has to be extended to family doctors in the community, where there is often a very high consumption of antibiotics. Relevant public health actions that are needed to reduce inappropriate antimicrobial prescriptions and antibiotic misuse should consider adequate information campaigns for the consumers, training of healthcare professionals, enhanced diagnostics to improve treatment decisions, the development of treatment guidelines, as well as regular prescription audits. In a nutshell, different healthcare organizations should strive to make coordinated efforts to institute new policies and put more emphasis on antimicrobial stewardship in professional curricula.
Image Credit: dturphoto/Shutterstock
You recently published research concerning the burden of bacterial antimicrobial resistance in the WHO European region. Can you tell us more about this study and the results you identified?
To our knowledge, this new study brings the most comprehensive analysis of the AMR burden in the WHO European region, and our estimates span across 53 countries, 23 bacterial pathogens, and 88 pathogen–drug combinations in 2019. There are several advances in comparison to previous work on this topic, primarily in scope (as not only the European Union is included, but all countries of the WHO European region), as well as in the number of included pathogen-drug combinations.
Furthermore, we used major methodological innovations that were first identified in the 2019 global burden of bacterial AMR study. The magnitude of the problem was described with the use of two scenarios, which means we provided estimates for both deaths directly caused by AMR (attributable mortality) and deaths that occurred from a drug-resistant infection, but for which AMR may or may not have been the cause (associated mortality).
Finally, our study allows comparisons with other causes of death since it builds on estimates of disease incidence, prevalence, and mortality from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019.
And results were striking. By identifying more than half a million deaths associated with AMR and more than 130 thousand deaths attributable to AMR, we have shown that antibiotic resistance is a considerable and potentially neglected problem in the WHO European region as a whole, with evident differences between subregions and specific countries. The largest fatal burden of AMR in the region came from bloodstream infections, followed by intra-abdominal infections and respiratory infections. The leading pathogens that we identified were (in descending order of death) Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa and Enterococcus faecium.
Such estimates of the impact of AMR on morbidity and mortality are crucial for informing public health investment decisions for each country in this region. Furthermore, highlighting specific pathogens and pathogen–drug combinations with the highest estimated burden – which we showed were methicillin-resistant Staphylococcus aureus (MRSA) and aminopenicillin-resistant Escherichia coli – might specifically inform policy targets and policy design. Our results emphasize that the most effective way to address AMR in this region will necessitate targeted efforts and investments, together with continuous outcome-based research endeavors.
Study: fizkes/Shutterstock
What do you believe are some of the challenges with approximating the magnitude of the AMR crisis and its downstream effect on human health?
There are indeed many challenges with this type of complex estimation process, and the biggest one is definitely data scarcity, as the availability of data on AMR can differ from one country to the next. This is not the only problem with our study but is universal for all research projects that aim to assess the burden of AMR. We also acknowledge that the effect of resistance on mortality may differ across locations, which can be pertinent when we pursue a global estimation of the AMR crisis.
More specifically, certain locations might not be well-suited to treat susceptible infections, which means that the effect of resistance is minimized; conversely, other locations might not have access to second-line antimicrobials; thus, the effect of resistance is magnified. It is also possible that the relative risk of death attributable to resistance can be different across anatomical sites of infection due to variable antibiotic penetrance.
Moreover, countries with low socio-demographic index (which is a summary measure that combines information on the education, economy, and fertility rate) might have much less stringent surveillance systems, as well as insufficient laboratory support – potentially resulting in an underestimation of attributable and associated AMR mortality globally and the countries of the WHO European Region. Nonetheless, our estimates are informed by data from all countries included in the study. When data for a specific country were lacking, estimates and model building relied on regional patterns, co-variates, and out-of-sample predictive validity.
Despite these limitations, our analysis reflects the widest and presently best available range of data, as well as the use of models that have been developed and implemented specifically for incorporating disparate data sources for the Global Burden of Disease analysis. We are in agreement with other studies that highlight and underscore critical data gaps on resistant organisms in certain parts of the world; therefore, solving this problem which will be extremely important in the future to fine-tune our estimates additionally.
WHO: What is antimicrobial resistance (AMR)?
The specific theme of World Antimicrobial Awareness Week (WAAW) 2022 is ‘Preventing antimicrobial resistance together.’ What does this theme mean to you personally, and how do you believe we can take steps toward this goal?
It is without any doubt that manifold joint efforts from healthcare workers (acting as prescribers) and patients to policymakers and international regulators are necessary to stand a chance against the global spread of antibiotic resistance. In other words, different stakeholders have to join forces in order to tackle this issue from many angles, as no single action will provide an acceptable solution in isolation.
Also, this issue is a truly global problem. Together with rational and prudent usage of currently available antimicrobial drugs and the introduction of antibiotics where there is a lack of them, the development of new and effective compounds, as well as the introduction of new diagnostic approaches, are all recognized as urgent priorities.
Governments should introduce several essential processes to inspire change by all stakeholders related to AMR, as appropriately described within the WHO policy package for combating drug resistance. More specifically, this policy package refers to a national plan that strives to be comprehensive, engages civil societies, and insists on the accountability of everyone involved. Also, strengthened surveillance systems, improved laboratory capacity, wide access to essential medicines of sufficient quality, regulated use of antibiotics, the emphasis on infection prevention and control, as well as promotion of innovations will be crucial in the near future. There has to be a commitment to a rather high level of human health protection.
How do you believe that different sectors, for example, healthcare, animal care, farming, and agriculture, can work collaboratively to help curb AMR?
Our quest against AMR should be addressed through the lens of a One Health approach. This means more stringent infection prevention/control in healthcare facilities, food industry premises, and farms, as well as insisting on best practices in agriculture, clean water, sanitation and waste management. A set of diverse but coordinated strategies against antibiotic resistance should be implemented, taking into account the type of pathogen (either human or zoonotic), the setting (healthcare or the community) and possibly other specific factors contributing to the emergence of resistance.
In veterinary medicine, the required interventions consist in enforcing regulations for improved surveillance and monitoring, governing the use of antimicrobials in food-producing animals, and decreasing the need for antibiotics through improved animal husbandry. Naturally, more research is needed to elucidate the exact pathways of transmission of resistant microbial agents between animals and humans (but also their subsequent impact). There is a need to adequately implement legislation if we are to achieve long-lasting effects.
In addition, innovative approaches are needed for the development of new antibiotics and other products to limit AMR. There is a shortage of new antibiotics in the pipeline and few incentives for the industry to invest in research and development in this field. Research into digital technologies and eHealth solutions has to be strengthened to improve prescription practices, care solutions, and overall awareness of this issue. All of this necessitates a well-designed roadmap to orchestrate further collaboration efforts between governments, industry, and non-governmental organizations.
Image Credit: AnaLysiSStudiO/Shutterstock
What are the next steps for you and your research? Do you have any exciting projects coming up?
The Global Research on AntiMicrobial resistance (GRAM) Project will definitely continue to be one of the most important global projects in years to come. Assessing the burden of bacterial antimicrobial resistance in the WHO European region in 2019 was our first regional endeavor, which will be followed by research publications covering other regions of the world. We believe it is of utmost importance to obtain a full picture of this pressing issue not only on a global but also on a regional and country level. In the future, one of the goals is to pursue a time-series analysis of the AMR burden through the years, which will be helpful in forecasting, preparedness planning, and key policy decisions.
Furthermore, we have already mentioned how the animal and environmental sectors present a plethora of opportunities for resistance to evolve and be introduced into human populations. Therefore, we believe it will be important to assess data gaps and links between animal and human resistance in one of our future projects. Our goal is also to assess significant indirect effects of AMR, such as the effect of AMR on antibiotic prophylaxis in transplant recipients or for the prevention of surgical site infections. One of the salient goals is to assess AMR in the context of health equity, particularly considering the results from the paper on the global burden of AMR.
Finally, there is a need to prioritize the improved collection of high-quality AMR data in both the human and animal sectors, as well as the environment, in order to improve all our future estimation processes. One of our goals is to facilitate data and resource sharing between countries to improve policy-making and capacity building. Finally, continuously broadening both the quantity and quality of data acquisition worldwide will allow us to monitor levels of resistance much more effectively and course-correct action where needed. We are confident that our data-driven approach will result in even more stringent estimates and help in tackling this enormous challenge.
Dr. Tomislav Meštrović is an Associate Professor at the University North in Croatia and an Affiliate Associate Professor at the Institute for Health Metrics and Evaluation (IHME) and the Department of Health Metrics Sciences of the University of Washington. He finished his medical and doctoral training at the University of Zagreb School of Medicine (Croatia), his MPH at the London School of Hygiene and Tropical medicine of the University of London (United Kingdom), and his MBA in International Healthcare Management at the Frankfurt School of Finance & Management (Germany). He is a board-certified clinical microbiology and sexual medicine specialist, with an additional one-year training in clinical research from Harvard Medical School.
His primary research interest with IHME is the public health significance and impact of antimicrobial resistance (AMR) within the Global Burden of Antimicrobial Resistance (GRAM) project, working in the AMR research team led by Professor Mohsen Naghavi. He joined this group as a Fulbright Visiting Scholar during the academic year 2021/2022, and was a lead author on the comprehensive assessment of AMR burden in the WHO European Region. Alongside his ongoing work in antibiotic resistance, he participates in other IHME-led and GBD-related projects, providing expertise for many pivotal global and public health research questions (particularly those in relation to infectious diseases). He is also a member of the WHO/HIFA Working Group Member on Learning for Quality Health Services, which is a part of the WHO Global Learning Laboratory (GLL) for Quality Universal Health Coverage (UHC).
IHME was established at the University of Washington in Seattle in 2007. Its mission is to deliver to the world timely, relevant, and scientifically valid evidence to improve health policy and practice.
A typical gut bacterium that can spread through the body and cause a serious infection resists natural immune defenses and antibiotics by enhancing its protective outer layer, known as the cell envelope, according to a new study by Weill Cornell Medicine investigators. The finding suggests possible new ways to target these bacterial infections.
The research, published Nov. 10 in mBio, illuminates some of the underlying changes that may occur when Enterococcus faecalis (E. faecalis) populations move through the epithelial cells lining of the intestine and escape to reach other body sites.
Systemic infections with E. faecalis can be lethal because this microbe has a remarkable ability to adapt to various environments and resist treatments.”
Dr. Diana K. Morales, principal investigator, assistant professor of microbiology and immunology in obstetrics and gynecology at Weill Cornell Medicine
People at risk of developing these infections include those who are taking antibiotics or who have compromised immune systems, which facilitate E. faecalis overgrowth in the intestine. Understanding how E. faecalis moves out of the gut and spreads may one day help scientists find small molecules to stop the bacterium’s extra-intestinal dissemination, preventing dangerous infections.
How the bacterium can move out of the intestine and to other organs has remained largely unexplored. However, researchers have observed that two different populations of the same species of bacterium exist, Dr. Morales said. One population develops traits that allow it to pass through the intestinal barrier acquiring an advantageous resistance to antimicrobials, while the other stays put.
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In a series of previous laboratory studies of the bacterium, the researchers found that motile E. faecalis produces molecules formed by sugar chains called polysaccharides that allow the bacterium to aggregate or clump together. “When these bacteria aggregate, they seem to develop an ability to move,” Dr. Morales said.
In the current study, the investigators, including lead author Dr. Yusibeska Ramos, a research associate in obstetrics and gynecology, found that the motile form of E. faecalis has a cell envelope containing increased amounts of glycolipids, which are fat molecules linked with a carbohydrate. Enhanced production of cell envelope glycolipids appears to help the bacterium to resist extracellular stressors. These stressors include the antimicrobial agent daptomycin, a common treatment for E. faecalis infection, and β-defensins, small molecules intestinal epithelial cells produce to deter infection.
The researchers also found that genetic mutations that inhibit glycolipid production made E. faecalis more sensitive to these stressors and reduced the ability of the bacterium to penetrate cell surfaces and move through intestinal epithelial cells.
The next step for the researchers is to evaluate additional in vivo models to confirm whether the molecular pathways uncovered in the current study are needed for the bacterium to exit the intestine. “We are also interested in identifying pharmacological approaches that can target these specific pathways with the goal of one day helping patients better fight infections by this gut microbe,” Dr. Morales said.
Ramos, Y., et al. (2022) Remodeling of the Enterococcal Cell Envelope during Surface Penetration Promotes Intrinsic Resistance to Stress. mBio.doi.org/10.1128/mbio.02294-22.
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Image Credit: dturphoto/Shutterstock
Study: fizkes/Shutterstock
Image Credit: AnaLysiSStudiO/Shutterstock
Metrics Sciences of the University of Washington. He finished his medical and doctoral training at the University of Zagreb School of Medicine (Croatia), his MPH at the London School of Hygiene and Tropical medicine of the University of London (United Kingdom), and his MBA in International Healthcare Management at the Frankfurt School of Finance & Management (Germany). He is a board-certified clinical microbiology and sexual medicine specialist, with an additional one-year training in clinical research from Harvard Medical School.