Antibiotic resistance is a global challenge that impacts all pharmaceutically used antibiotics. The origin of the genes associated with this resistance is of significant importance to our understanding of the evolution and dissemination of antibiotic resistance in pathogens. A growing body of evidence implicates environmental organisms as reservoirs of these resistance genes; however, the role of anthropogenic use of antibiotics in the emergence of these genes is controversial. We report a screen of a sample of the culturable microbiome of Lechuguilla Cave, New Mexico, in a region of the cave that has been isolated for over 4 million years. We report that, like surface microbes, these bacteria were highly resistant to antibiotics; some strains were resistant to 14 different commercially available antibiotics. Resistance was detected to a wide range of structurally different antibiotics including daptomycin, an antibiotic of last resort in the treatment of drug resistant Gram-positive pathogens. Enzyme-mediated mechanisms of resistance were also discovered for natural and semi-synthetic macrolide antibiotics via glycosylation and through a kinase-mediated phosphorylation mechanism. Sequencing of the genome of one of the resistant bacteria identified a macrolide kinase encoding gene and characterization of its product revealed it to be related to a known family of kinases circulating in modern drug resistant pathogens. The implications of this study are significant to our understanding of the prevalence of resistance, even in microbiomes isolated from human use of antibiotics. This supports a growing understanding that antibiotic resistance is natural, ancient, and hard wired in the microbial pangenome.

Hepatocellular carcinoma (HCC) arises on the background of chronic liver disease. Despite the development of effective anti-viral therapeutics HCC is continuing to rise, in part driven by the epidemic of non-alcoholic fatty liver disease. Many patients present with advanced disease out with the criteria for transplant, resection or even locoregional therapy. Currently available therapeutics for HCC are effective in a small minority of individuals. However, there has been a major global interest in immunotherapies for cancer and although HCC has lagged behind other cancers, great opportunities now exist for treating HCC with newer and more sophisticated agents. Whilst checkpoint inhibitors are at the forefront of this revolution, other therapeutics such as inhibitory cytokine blockade, oncolytic viruses, adoptive cellular therapies and vaccines are emerging. Broadly these may be categorized as either boosting existing immune response or stimulating de novo immune response. Although some of these agents have shown promising results as monotherapy in early phase trials it may well be that their future role will be as combination therapy, either in combination with one another or in combination with treatment modalities such as locoregional therapy. Together these agents are likely to generate new and exciting opportunities for treating HCC, which are summarized in this review.

BackgroundThe Candidate Phyla Radiation (CPR) is a recently described expansion of the tree of life that represents more than 15% of all bacterial diversity and potentially contains over 70 different phyla. Despite this broad phylogenetic variation, these microorganisms appear to feature little functional diversity, with members generally characterized as obligate fermenters. Additionally, much of the data describing CPR phyla has been generated from a limited number of environments, constraining our knowledge of their functional roles and biogeographical distribution. To expand our understanding of subsurface CPR microorganisms, we sampled four separate groundwater wells over 2 years across three Ohio counties.ResultsSamples were analyzed using 16S rRNA gene amplicon and shotgun metagenomic sequencing. Amplicon results indicated that CPR members comprised between 2 and 20% of the microbial communities with relative abundances stable through time in Athens and Greene samples but dynamic in Licking groundwater. Shotgun metagenomic analyses generated 71 putative CPR genomes, representing roughly 32 known phyla and 2 putative new phyla, Candidatus Brownbacteria and Candidatus Hugbacteria. While these genomes largely mirrored metabolic characteristics of known CPR members, some features were previously uncharacterized. For instance, nitrite reductase, encoded by nirK, was found in four of our Parcubacteria genomes and multiple CPR genomes from other studies, indicating a potentially undescribed role for these microorganisms in denitrification. Additionally, glycoside hydrolase (GH) family profiles for our 71 genomes and over 2000 other CPR genomes were analyzed to characterize their carbon-processing potential. Although common trends were present throughout the radiation, differences highlighted potential mechanisms that could allow microorganisms across the CPR to occupy various subsurface niches. For example, members of the Microgenomates superphylum appear to potentially degrade a wider range of carbon substrates than other CPR phyla.ConclusionsCPR members are present across a range of environments and often constitute a significant fraction of the microbial population in groundwater systems, particularly. Further sampling of such environments will resolve this portion of the tree of life at finer taxonomic levels, which is essential to solidify functional differences between members that populate this phylogenetically broad region of the tree of life.Electronic supplementary materialThe online version of this article (10.1186/s40168-017-0331-1) contains supplementary material, which is available to authorized users.

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Rising seawater temperature and ocean acidification threaten the survival of coral reefs. The relationship between coral physiology and its microbiome may reveal why some corals are more resilient to these global change conditions. Here, we conducted the first experiment to simultaneously investigate changes in the coral microbiome and coral physiology in response to the dual stress of elevated seawater temperature and ocean acidification expected by the end of this century. Two species of corals, Acropora millepora containing the thermally sensitive endosymbiont C21a and Turbinaria reniformis containing the thermally tolerant endosymbiont Symbiodinium trenchi, were exposed to control (26.5°C and pCO2 of 364 μatm) and treatment (29.0°C and pCO2 of 750 μatm) conditions for 24 days, after which we measured the microbial community composition. These microbial findings were interpreted within the context of previously published physiological measurements from the exact same corals in this study (calcification, organic carbon flux, ratio of photosynthesis to respiration, photosystem II maximal efficiency, total lipids, soluble animal protein, soluble animal carbohydrates, soluble algal protein, soluble algal carbohydrate, biomass, endosymbiotic algal density, and chlorophyll a). Overall, dually stressed A. millepora had reduced microbial diversity, experienced large changes in microbial community composition, and experienced dramatic physiological declines in calcification, photosystem II maximal efficiency, and algal carbohydrates. In contrast, the dually stressed coral T. reniformis experienced a stable and more diverse microbiome community with minimal physiological decline, coupled with very high total energy reserves and particulate organic carbon release rates. Thus, the microbiome changed and microbial diversity decreased in the physiologically sensitive coral with the thermally sensitive endosymbiotic algae but not in the physiologically tolerant coral with the thermally tolerant endosymbiont. Our results confirm recent findings that temperature-stress tolerant corals have a more stable microbiome, and demonstrate for the first time that this is also the case under the dual stresses of ocean warming and acidification. We propose that coral with a stable microbiome are also more physiologically resilient and thus more likely to persist in the future, and shape the coral species diversity of future reef ecosystems.