Editorial Cite This: ACS Infect. Dis. 2018, 4, 1−2
pubs.acs.org/journal/aidcbc
The Human Microbiome
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metagenomic clone library carrying DNA from the human gut microbiome for antibiotic activity toward E. coli reveals a gut microbial gene cluster that encodes for the bacteriocin colicin V. This peptide narrowly targets E. coli and may have an important ecological role in the gut. Such bacteriocins also represent a potential source of narrow-spectrum antibiotics that could limit collateral damage to the microbiome. Second, Brady and co-workers have directly synthesized the predicted products of natural product biosynthetic gene clusters from members of human microbiome (DOI: 10.1021/acsinfecdis.7b00056). This approach had previously identified humimycin, an antibiotic that is active against Staphlococcus aureus and targets the key flippase MurJ involved in cell wall biosynthesis. Here, they analyze the structure−activity relationship of humimycin, gaining insights into its activity and accessing additional active analogs. One of the humimycin analogs displays increased potency as a potentiator of β-lactam antibiotics. Together, these three studies illustrate that mammal-associated microbiomes are an exciting, untapped venue for antimicrobial discovery. In addition to mining the human microbiome for bioactive small molecules and proteins, there has been growing excitement surrounding the possibility of using these organisms as therapeutic agents. Fueled by the success of fecal microbiome transplant in treating recurrent C. dif f icile infections, researchers are interested in employing both defined microbial consortia and individual, engineered microbial strains to prevent or treat human disease. However, a major challenge in implementing this approach is the problem of predicting and controlling the activities of these organisms in the context of the human host. Two studies in this issue address this obstacle in different ways. Davies and co-workers (DOI: 10.1021/ acsinfecdis.7b00127) examine a probiotic strain of E. coli engineered to synthesize N-acyl-phosphatidylethanolamines (NAPEs), a class of lipids normally made by the host. NAPEs are converted to signaling molecules that regulate satiety and protect against obesity. By systematically examining the factors affecting NAPE production, they unveil a key role for dietary fatty acids in dictating the precise composition of NAPEs generated in vivo, highlighting the potential of using host diet to control and enhance the activity of engineered probiotics. In addition to producing molecules that affect host cells, engineered probiotic strains can also target other microbes. Bucci and co-workers (DOI: 10.1021/acsinfecdis.7b00114) explore the use of engineered E. coli to combat pathogenic Salmonella. They construct a strain that couples production of the antimicrobial peptide microcin H47 to the sensing and use of tetrathionate, a terminal electron acceptor generated in the inflamed human gut in response to Salmonella. Their engineered E. coli strain can inhibit and outcompete Salmonella in vitro. Together, these studies illustrate how a
rillions of microorganisms live in and on the human body, with the human gastrointestinal tract harboring one of the densest microbial habitats known. These complex and variable microbial communities are referred to as the human microbiome. While we have known about the presence of these organisms since the birth of microbiology, only within the last two decades have we gained a detailed understanding of the compositions of human-associated microbial communities. These recent efforts have also uncovered numerous correlations between the human microbiome and disease, including numerous infectious diseases. Overall, it is becoming clear that we cannot fully understand human biology without considering these organisms. This area of science currently stands at an exciting but challenging point. While we have gained a descriptive understanding of human-associated microbial communities, we have not yet elucidated the molecular mechanisms underlying their effects on host biology. This information is needed to realize the tremendous potential of these organisms to improve human health. As studies of the human microbiome shift from a focus on community composition to the biological functions of these organisms, it is becoming clear that contributions from many scientific disciplines are needed to address this enormous knowledge gap. This Special Issue on The Microbiome highlights how this rapidly evolving field of research is revealing new opportunities for understanding and combatting human disease, including infectious diseases. It also seeks to illuminate the central role that chemists can play in efforts to understand and harness these microbial communities. One major area of investigation with the potential to impact infectious disease is the discovery of antimicrobial agents from human-associated microbes. Though it has long been appreciated that production of antimicrobial substances plays an important role in microbial communities, little is known about this phenomenon in the gut microbiomes of humans or other mammals. Identifying and characterizing antimicrobials produced by members of the human microbiome may advance our understanding of the ecology of these communities. Molecules from gut organisms could also be a source of new therapeutics. With this latter goal in mind, Linington and coworkers (DOI: 10.1021/acsinfecdis.7b00105) turn to an untapped resource: the gut microbiomes of marine mammals. By screening a collection of gut isolates from these animals, they uncover phocoenamicin, a new member of the spirotetronate family of antibiotics. This molecule has potent activity toward Gram-positive pathogens, including Clostridium dif f icile. Though culturable organisms may be a promising source of antimicrobial compounds, the difficulties encountered in cultivating many microbes present a prominent obstacle in studying microbiomes. Brady and co-workers address this problem in the context of antibiotic discovery using two different strategies. First, they employ a functional metagenomics approach to discover antibacterial agents from human gut microbes (DOI: 10.1021/acsinfecdis.7b00081). Screening a © 2018 American Chemical Society
Special Issue: The Microbiome Received: November 26, 2017 Published: January 12, 2018 1
DOI: 10.1021/acsinfecdis.7b00248 ACS Infect. Dis. 2018, 4, 1−2
ACS Infectious Diseases
Editorial
threaten global health, including tuberculosis, malaria, HIV, and enteric diseases. We not only review recent work aimed at elucidating how these microbial communities affect infectious disease risk, but also highlight avenues for future research that could unveil new strategies for combatting these agents. Notably, we discuss communities beyond the human gut, including the lung, skin, penile, and vaginal microbiomes. Though understudied relative to the gut microbiome, it is becoming clear that these microbial communities also present rich opportunities for further study and therapeutic development. In order to gain a mechanistic understanding of the human microbiome, it is essential that we begin to view these communities as molecular entities. It is my hope that this Special Issue of ACS Infectious Diseases will generate excitement for this emerging research area among chemists, enticing them to begin exploring these amazing, complex microbial assemblages. I am grateful to the authors and reviewers who have contributed to this special issue. Their inspiring work showcases how the discipline of chemistry is uniquely positioned to enable an exciting new era in human microbiome research.
molecular understanding of commensal, pathogen, and host metabolism can enhance the design and deployment of engineered microbial therapeutics. Beyond just providing new sources of therapeutics, the human gut microbiome can influence the efficacy of small molecule drugs and other ingested, foreign compounds (xenobiotics). One mechanism by which this occurs is through the direct metabolism of drugs. These gut microbial transformations are often chemically distinct from host drug metabolism and can alter drug activity, toxicity, and distribution. Interindividual differences in gut microbial drug metabolism may affect patients’ response to therapeutics, and an increased understanding of these interactions could enable personalized medicine. However, we currently have a limited understanding of the range of drugs that are subject to gut microbial processing. In this issue, Wright and co-workers (DOI: 10.1021/acsinfecdis.7b00166) report the discovery of an anaerobic route for degradation of the anticancer agent doxorubicin by gut bacteria. They link this metabolic activity to molybdenum cofactor-containing enzymes and show that doxorubicin-metabolizing gut bacteria reduce the toxicity of doxorubicin to Caenorhabitis elegans. An understanding of this transformation in the human gut could inform strategies to reduce the toxicity of this important cancer chemotherapeutic. In addition to direct interactions with the gut microbiome, drugs can also indirectly affect this microbial community. Redinbo, Allbritton, and co-workers (DOI: 10.1021/acsinfecdis.7b00139) uncover one such interaction while exploring the effect of the nonsteroidal anti-inflammatory agent (NSAID) diclofenac on host intestinal epithelium. Using a newly developed model system consisting of human primary small intestinal cell monolayers, they discover that diclofenac treatment increases gut barrier permeability. This change in cell physiology likely exposes the host to increased amounts of immunostimulatory gut microbial products, including lipopolysaccharide. This work not only shows how drugs may alter host interactions with the gut microbiome, but also highlights the importance of developing new model systems to study the human gut epithelium. In addition to mediating interactions with the human host, molecules produced by gut bacteria can also impact other organisms in this community, including fungi. For example, fragments of peptidoglycan affect the transition of the commensal fungal strain Candida albicans from a nonpathogenic, budding form to a filamentous, hyphae form that can form biofilms, become invasive, and cause infections. Grimes and co-workers (DOI: 10.1021/acsinfecdis.7b00154) provide new insights into this transition by characterizing binding of bacterially derived carbohydrates to a leucine-rich repeat domain of Cyr1, an adenylate cyclase that is the key regulator of this transition. By showing that a diverse range of carbohydrates can bind to Cyr1, these findings lay the groundwork for understanding how interactions within the dynamic environment of the human gut affect fungal pathogenesis. These contributions highlight the various ways in which chemists are currently contributing to human microbiome research. Looking ahead, what are the most exciting, emerging opportunities for future investigations of the microbiome’s role in infectious disease? In a Perspective, Waldman and Balskus (DOI: 10.1021/acsinfecdis.7b00232) describe how a growing understanding of both human and vector microbiomes may change how we prevent and treat infectious diseases that
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Emily P. Balskus
AUTHOR INFORMATION
ORCID
Emily P. Balskus: 0000-0001-5985-5714 Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS.
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DOI: 10.1021/acsinfecdis.7b00248 ACS Infect. Dis. 2018, 4, 1−2
