Why Do Antibiotics Exist?

In the struggle with antibiotic resistance, we are losing. There is now a serious threat of moving into a postantibiotic world. High levels of resistance, in terms of both frequency and strength, have evolved against all clinically approved antibiotics worldwide. The usable life span of new clinically approved antibiotics is typically less than a decade before resistance reaches frequencies so high as to require only guarded usage. However, microbes have produced antibiotics for millennia without resistance becoming an existential issue. If resistance is the inevitable consequence of antibiotic usage, as has been the human experience, why has it not become an issue for microbes as well, especially since resistance genes are as prevalent in nature as the genes responsible for antibiotic production? Here, we ask how antibiotics can exist given the almost ubiquitous presence of resistance genes in the very microbes that have produced and used antibiotics since before humans walked the planet. We find that the context of both production and usage of antibiotics by microbes may be key to understanding how resistance is managed over time, with antibiotic synthesis and resistance existing in a paired relationship, much like a cipher and key, that impacts microbial community assembly. Finally, we put forward the cohesive, ecologically based "secret society" hypothesis to explain the longevity of antibiotics in nature.

SARS-CoV-2, Zika viruses and mycoplasma: Structure, pathogenesis and some treatment options in these emerging viral and bacterial infectious diseases.

The molecular evolution of life on earth along with changing environmental, conditions has rendered mankind susceptible to endemic and pandemic emerging infectious diseases. The effects of certain systemic viral and bacterial infections on morbidity and mortality are considered as examples of recent emerging infections. Here we will focus on three examples of infections that are important in pregnancy and early childhood: SARS-CoV-2 virus, Zika virus, and Mycoplasma species. The basic structural characteristics of these infectious agents will be examined, along with their general pathogenic mechanisms. Coronavirus infections, such as caused by the SARS-CoV-2 virus, likely evolved from zoonotic bat viruses to infect humans and cause a pandemic that has been the biggest challenge for humanity since the Spanish Flu pandemic of the early 20th century. In contrast, Zika Virus infections represent an expanding infectious threat in the context of global climate change. The relationship of these infections to pregnancy, the vertical transmission and neurological sequels make these viruses highly relevant to the topics of this special issue. Finally, mycoplasmal infections have been present before mankind evolved, but they were rarely identified as human pathogens until recently, and they are now recognized as important coinfections that are able to modify the course and prognosis of various infectious diseases and other chronic illnesses. The infectious processes caused by these intracellular microorganisms are examined as well as some general aspects of their pathogeneses, clinical presentations, and diagnoses. We will finally consider examples of treatments that have been used to reduce morbidity and mortality of these infections and discuss briefly the current status of vaccines, in particular, against the SARS-CoV-2 virus. It is important to understand some of the basic features of these emerging infectious diseases and the pathogens involved in order to better appreciate the contributions of this special issue on how infectious diseases can affect human pregnancy, fetuses and neonates.

Antimicrobial resistance: more than 70 years of war between humans and bacteria.

Development of antibiotic resistance in bacteria is one of the major issues in the present world and one of the greatest threats faced by mankind. Resistance is spread through both vertical gene transfer (parent to offspring) as well as by horizontal gene transfer like transformation, transduction and conjugation. The main mechanisms of resistance are limiting uptake of a drug, modification of a drug target, inactivation of a drug, and active efflux of a drug. The highest quantities of antibiotic concentrations are usually found in areas with strong anthropogenic pressures, for example medical source (e.g., hospitals) effluents, pharmaceutical industries, wastewater influents, soils treated with manure, animal husbandry and aquaculture (where antibiotics are generally used as in-feed preparations). Hence, the strong selective pressure applied by antimicrobial use has forced microorganisms to evolve for survival. The guts of animals and humans, wastewater treatment plants, hospital and community effluents, animal husbandry and aquaculture runoffs have been designated as "hotspots for AMR genes" because the high density of bacteria, phages, and plasmids in these settings allows significant genetic exchange and recombination. Evidence from the literature suggests that the knowledge of antibiotic resistance in the population is still scarce. Tackling antimicrobial resistance requires a wide range of strategies, for example, more research in antibiotic production, the need of educating patients and the general public, as well as developing alternatives to antibiotics (briefly discussed in the conclusions of this article).

[Epidemics: lessons from History]. / Épidémies: Leçons d'Histoire.

TITLE: Épidémies: Leçons d'Histoire. ABSTRACT: Jusqu'au milieu du XVIIIe siècle, l'espérance de vie était de 25 ans dans les pays d'Europe, proche alors de celle de la préhistoire. À cette époque, nos ancêtres succombaient, pour la plupart, à une infection bactérienne ou virale, quand la mort n'était pas le résultat d'un épisode critique, comme la guerre ou la famine. Un seul microbe suffisait à terrasser de nombreuses victimes. L'épidémie de SARS-CoV-2 est là pour nous rappeler que ce risque est désormais à nouveau d'actualité. Si son origine zoonotique par la chauve-souris est probable, la contamination interhumaine montre son adaptation rapide à l'homme et permet d'évoquer ainsi la transmission des épidémies, qu'elle soit ou non liée à des vecteurs, ces derniers pouvant représenter dans d'autres occasions un des maillons de la chaîne.

Candidatus Cryptoplasma Associated with Green Lizards and Ixodes ricinus Ticks, Slovakia, 2004-2011.

During 2004-2011, we collected green lizards and Ixodes ricinus ticks in Slovak Karst National Park in Slovakia; 90% (36/40) of lizards and 37% of ticks removed from lizards were infected with family Anaplasmataceae bacteria. Only Candidatus Cryptoplasma sp. REP (reptile) was identified in these samples. Green lizards transmit this bacterium.

An Alternative Cure: The Adoption and Survival of Bacteriophage Therapy in the USSR, 1922-1955.

Felix D'Herelle coined the term bacteriophage in 1917 to characterize a hypothetical viral agent responsible for the mysterious phenomenon of rapid bacterial death. While the viral nature of the "phage" was only widely accepted in the 1940s, attempts to use the phenomenon in treating infections started early. After raising hopes in the interwar years, by 1945 phage therapy had been abandoned almost entirely in the West, until the recent revival of interest in response to the crisis of antibiotic resistance. The use of phage therapy, however, persisted within Soviet medicine, especially in Georgia. This article explains the adoption and survival of phage therapy in the USSR. By focusing on the Tbilisi Institute of Microbiology, Epidemiology and Bacteriophage (now the Eliava Institute), I argue that bacteriophage research appealed to Soviet scientists because it offered an ecological model for understanding bacterial infection. In the 1930s, phage therapy grew firmly imbedded within the infrastructure of Soviet microbiological institutes. During the Second World War, bacteriophage preparations gained practical recognition from physicians and military authorities. At the dawn of the Cold War, the growing scientific isolation of Soviet science protected phage therapy from the contemporary western critiques, and the ecological program of research into bacteriophages continued in Georgia.

Limited Innovations After More Than 65 Years of Immunoglobulin Replacement Therapy: Potential of IgA- and IgM-Enriched Formulations to Prevent Bacterial Respiratory Tract Infections.

Patients with primary immunoglobulin deficiency have lower immunoglobulin levels or decreased immunoglobulin function, which makes these patients more susceptible to bacterial infection. Most prevalent are the selective IgA deficiencies (~1:3,000), followed by common variable immune deficiency (~1:25,000). Agammaglobulinemia is less common (~1:400,000) and is characterized by very low or no immunoglobulin production resulting in a more severe disease phenotype. Therapy for patients with agammaglobulinemia mainly relies on prophylactic antibiotics and the use of IgG replacement therapy, which successfully reduces the frequency of invasive bacterial infections. Currently used immunoglobulin preparations contain only IgG. As a result, concurrent IgA and IgM deficiency persist in a large proportion of agammaglobulinemia patients. Especially patients with IgM deficiency remain at risk for recurrent infections at mucosal surfaces, which includes the respiratory tract. IgA and IgM have multiple functions in the protection against bacterial infections at the mucosal surface. Because of their multimeric structure, both IgA and IgM are able to agglutinate bacteria efficiently. Agglutination allows for entrapment of bacteria in mucus that increases clearance from the respiratory tract. IgA is also important for blocking bacterial adhesion by interfering with bacterial adhesion receptors. IgM in its place is very well capable of activating complement, therefore, it is thought to be important in complement-mediated protection at the mucosal surface. The purpose of this Mini Review is to highlight the latest advances regarding IgA- and IgM-enriched immunoglobulin replacement therapy. We describe the different IgA- and IgM-enriched IgG formulations, their possible modes of action and potential to protect against respiratory tract infections in patients with primary immunoglobulin deficiencies.

Fitting the message to the location: engaging adults with antimicrobial resistance in a World War 2 air raid shelter.

AIMS: There are many different initiatives, global and local, designed to raise awareness of antimicrobial resistance (AMR) and change audience behaviour. However, it is not possible to assess the impact of specific, small-scale events on national and international outcomes-although one might acknowledge some contribution to the individual and collective knowledge and experience-focused 'science capital' As with any research, in preparation for a public engagement event, it is important to identify aims, and appropriate methods whose results might help satisfy those aims. Therefore, the aim of this paper was to develop, deliver and evaluate an event designed to engage an adult audience with AMR. METHODS AND RESULTS: The venue was a World War 2 air raid shelter, enabling comparison of the pre- and postantibiotic eras via three different activity stations, focusing on nursing, the search for new antibiotics and investigations into novel antimicrobials. The use of observers released the presenters from evaluation duties, enabling them to focus on their specific activities. Qualitative measures of audience engagement were combined with quantitative data. CONCLUSIONS: The evaluation revealed that adult audiences can easily be absorbed into an activity-particularly if hands-on-after a brief introduction. SIGNIFICANCE AND IMPACT OF THE STUDY: This research demonstrates that hands-on practical engagement with AMR can enable high-level interaction and learning in an informal and enjoyable environment.

Georgy Gause's shift from ecology and evolutionary biology to antibiotics research: reasons, objectives, circumstances.

Georgy Gause (1910-1986) is best known for his contribution to ecology and evolutionary theory. His book "The Struggle for Existence" (1934) inspired generations of ecologists. Yet his scientific interests were diverse, embracing many aspects of the life sciences and medicine. The most notable shift in his research took place in the early 1940s when he began to study antibiotics and discovered Gramicidin S. Superficially, this shift looked like an attempt to switch from purely theoretical to applied research during the years of World War II, but Gause's decision may also have been seriously affected by the "Great Purge" and the growth of Lysenkoism. Personal factors played a significant role in his career too. In this article, we propose four factors which drove Gause to switch his focus from ecology to antibiotics: the inner logic of his scientific research, Stalin's science policy and the growth of Lysenkoism, the sociopolitical influence of World War II, and personal relationships. We will also show how all these factors are interdependent to some extent.

Bacterial Infections in Neonates, Madagascar, 2012-2014.

Severe bacterial infections are a leading cause of death among neonates in low-income countries, which harbor several factors leading to emergence and spread of multidrug-resistant bacteria. Low-income countries should prioritize interventions to decrease neonatal infections; however, data are scarce, specifically from the community. To assess incidence, etiologies, and antimicrobial drug-resistance patterns of neonatal infections, during 2012-2014, we conducted a community-based prospective investigation of 981 newborns in rural and urban areas of Madagascar. The incidence of culture-confirmed severe neonatal infections was high: 17.7 cases/1,000 live births. Most (75%) occurred during the first week of life. The most common (81%) bacteria isolated were gram-negative. The incidence rate for multidrug-resistant neonatal infection was 7.7 cases/1,000 live births. In Madagascar, interventions to improve prevention, early diagnosis, and management of bacterial infections in neonates should be prioritized.

The history and promising future of phage therapy in the military service.

The continuous evolvement of bacterial resistance to most, if not all, available antibiotics is a worldwide problem. These strains, frequently isolated from military-associated environments, have created an urgent need to develop supplementary anti-infective modalities. One of the leading directions is phage therapy, which includes the administration of bacteriophages, viruses that specifically target bacteria, as biotherapies. Although neglected in the West until recent years, bacteriophages have been widely studied and clinically administered in the former Soviet Union and Eastern Europe for over a century, where they were found to be incredibly efficient at battling numerous infectious diseases.In this review, we discuss the high potential of phage therapy as a solution for resistant bacterial infectious diseases relating to military medicine. By describing the historical development and knowledge acquired on phage therapy, we define the advantages of bacteriophages for combating resistant bacteria in multiple settings, such as trauma injuries and foodborne illnesses, as a preventive tool and therapy against biological warfare agents, and more. We also present the most recent successful clinical applications of bacteriophages in military settings worldwide.We believe that augmenting military medicine by integrating phage therapy is an important and required step in preparedness for the rapidly approaching post-antibiotic era.

Reemergence of the Natural History of Otolaryngologic Infections: Lessons Learned from 2 American Presidents.

Presidents George Washington and Theodore Roosevelt suffered complications of epiglottitis and otomastoiditis, respectively. The introduction of antibiotics and vaccinations against Haemophilus influenzae and Streptococcus pneumoniae has significantly reduced the incidence of these otolaryngologic infections, such that the natural history of the disease is rarely encountered. However, antibiotic resistance and pathogenic evolution has raised concern about increased virulence of these common organisms. A retrospective evaluation of the complications suffered by Washington and Roosevelt provides valuable insight to the natural history of common otolaryngologic infections that may reemerge as a result of organism evolution in response to antibiotics and vaccines.

Antibacterial activity of medicinal plants from The Physicians of Myddvai, a 14th century Welsh medical manuscript.

ETHNOPHARMACOLOGICAL RELEVANCE: Antimicrobial drug resistance is a growing threat to global public health. Historical records and herbal texts relating to traditional Celtic medicine indicate an extensive pharmacopeia of plants for treating infections likely caused by microbes. However, a major barrier for successful integration of these remedies into mainstream practice is the current lack of accurate interpretation and scientific validation. MATERIALS AND METHODS: We investigated the flora of the Isle of Arran, Scotland, via in situ targeted screening of 83 out of 138 plants identified in Meddygion Myddvai (a 14th century Welsh manuscript) to treat conditions related to microbial infections, and an additional 18 plants from modern ethnobotanical knowledge on the island (Scottish School of Herbal Medicine). In a follow-up proof-of-concept study, bioassay-guided fractionation was performed to identify bioactive constituents from two high scoring hits that inhibited Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative) bacterial growth. RESULTS: 67 historical plants (80.7%) and 14 modern plants (77.8%) were found to have detectable levels of antimicrobial activity when tested using Mobile Discovery kits, with human saliva as a source of bacteria for screening. Sabinene, a natural bicyclic monoterpene from juniper "berries" (Juniperus communis L.) and alliin, a natural sulfoxide from garlic cloves (Allium sativum L.), were isolated and confirmed as primary antibacterial leads. CONCLUSION: Using historical medical sources such as those associated with traditional Celtic medicine to guide rigorous, evidence-based scientific investigation, provides additional leads for new and alternative bioactive molecules for combating bacterial diseases.

A re-appraisal of the conventional history of antibiosis and Penicillin.

The popular perception of the history of antibiosis and penicillin is that Alexander Fleming was the sole researcher on penicillin. The literature, however, has documentation of preceding persons who reported definitively on these topics, from the late 19th century. Divergent reports on "firsts" in the discovery of antimicrobial activity of Penicillium and on the use of penicillin as a therapeutic agent, are present. This review adds knowledge from diverse sources, and restores historical priorities to the conventional story of Penicillin.