An Orally Delivered Beta-Lactamase Protects the Gut Microbiome from Antibiotic-Mediated Damage and Mitigates the Propagation of Antibiotic-Resistance Genes in a Porcine Dysbiosis Model

2017 ◽  
Vol 152 (5) ◽  
pp. S1305-S1306
Author(s):  
Sheila Connelly ◽  
Christian Furlan Freguia ◽  
Poorani Subramanian ◽  
Nur A. Hasan ◽  
Rita R. Colwell ◽  
...  
2019 ◽  
Vol 7 (5) ◽  
pp. 150 ◽  
Author(s):  
Sheila Connelly ◽  
Brian Fanelli ◽  
Nur A. Hasan ◽  
Rita R. Colwell ◽  
Michael Kaleko

Antibiotics damage the gut microbiome, which can result in overgrowth of pathogenic microorganisms and emergence of antibiotic resistance. Inactivation of antibiotics in the small intestine represents a novel strategy to protect the colonic microbiota. SYN-004 (ribaxamase) is a beta-lactamase formulated for oral delivery intended to degrade intravenously administered beta-lactam antibiotics in the gastrointestinal (GI) tract. The enteric coating of ribaxamase protects the enzyme from stomach acid and mediates pH-dependent release in the upper small intestine, the site of antibiotic biliary excretion. Clinical benefit was established in animal and human studies in which ribaxamase was shown to degrade ceftriaxone in the GI tract, thereby preserving the gut microbiome, significantly reducing Clostridioides difficile disease, and attenuating antibiotic resistance. To expand ribaxamase utility to oral beta-lactams, delayed release formulations of ribaxamase, SYN-007, were engineered to allow enzyme release in the lower small intestine, distal to the site of oral antibiotic absorption. Based on in vitro dissolution profiles, three SYN-007 formulations were selected for evaluation in a canine model of antibiotic-mediated gut dysbiosis. Dogs received amoxicillin (40 mg/kg, PO, TID) +/- SYN-007 (10 mg, PO, TID) for five days. Serum amoxicillin levels were measured after the first and last antibiotic doses and gut microbiomes were evaluated using whole genome shotgun sequence metagenomics analyses of fecal DNA prior to and after antibiotic treatment. Serum amoxicillin levels did not significantly differ +/- SYN-007 after the first dose for all SYN-007 formulations, while only one SYN-007 formulation did not significantly reduce systemic antibiotic concentrations after the last dose. Gut microbiomes of animals receiving amoxicillin alone displayed significant loss of diversity and emergence of antibiotic resistance genes. In contrast, for animals receiving amoxicillin + SYN-007, microbiome diversities were not altered significantly and the presence of antibiotic resistance genes was reduced. These data demonstrate that SYN-007 diminishes amoxicillin-mediated microbiome disruption and mitigates emergence and propagation of antibiotic resistance genes without interfering with antibiotic systemic absorption. Thus, SYN-007 has the potential to protect the gut microbiome by inactivation of beta-lactam antibiotics when administered by both oral and parenteral routes and to reduce emergence of antibiotic-resistant pathogens.


2017 ◽  
Author(s):  
Sumayah F. Rahman ◽  
Matthew R. Olm ◽  
Michael J. Morowitz ◽  
Jillian F. Banfield

AbstractAntibiotic resistance in pathogens is extensively studied, yet little is known about how antibiotic resistance genes of typical gut bacteria influence microbiome dynamics. Here, we leverage genomes from metagenomes to investigate how genes of the premature infant gut resistome correspond to the ability of bacteria to survive under certain environmental and clinical conditions. We find that formula feeding impacts the resistome. Random forest models corroborated by statistical tests revealed that the gut resistome of formula-fed infants is enriched in class D beta-lactamase genes. Interestingly,Clostridium difficilestrains harboring this gene are at higher abundance in formula-fed infants compared toC. difficilelacking this gene. Organisms with genes for major facilitator superfamily drug efflux pumps have faster replication rates under all conditions, even in the absence of antibiotic therapy. Using a machine learning approach, we identified genes that are predictive of an organism’s direction of change in relative abundance after administration of vancomycin and cephalosporin antibiotics. The most accurate results were obtained by reducing annotated genomic data into five principal components classified by boosted decision trees. Among the genes involved in predicting if an organism increased in relative abundance after treatment are those that encode for subclass B2 beta-lactamases and transcriptional regulators of vancomycin resistance. This demonstrates that machine learning applied to genome-resolved metagenomics data can identify key genes for survival after antibiotics and predict how organisms in the gut microbiome will respond to antibiotic administration.ImportanceThe process of reconstructing genomes from environmental sequence data (genome-resolved metagenomics) allows for unique insight into microbial systems. We apply this technique to investigate how the antibiotic resistance genes of bacteria affect their ability to flourish in the gut under various conditions. Our analysis reveals that strain-level selection in formula-fed infants drives enrichment of beta-lactamase genes in the gut resistome. Using genomes from metagenomes, we built a machine learning model to predict how organisms in the gut microbial community respond to perturbation by antibiotics. This may eventually have clinical and industrial applications.


Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Yu Li ◽  
Zeling Xu ◽  
Wenkai Han ◽  
Huiluo Cao ◽  
Ramzan Umarov ◽  
...  

Abstract Background The spread of antibiotic resistance has become one of the most urgent threats to global health, which is estimated to cause 700,000 deaths each year globally. Its surrogates, antibiotic resistance genes (ARGs), are highly transmittable between food, water, animal, and human to mitigate the efficacy of antibiotics. Accurately identifying ARGs is thus an indispensable step to understanding the ecology, and transmission of ARGs between environmental and human-associated reservoirs. Unfortunately, the previous computational methods for identifying ARGs are mostly based on sequence alignment, which cannot identify novel ARGs, and their applications are limited by currently incomplete knowledge about ARGs. Results Here, we propose an end-to-end Hierarchical Multi-task Deep learning framework for ARG annotation (HMD-ARG). Taking raw sequence encoding as input, HMD-ARG can identify, without querying against existing sequence databases, multiple ARG properties simultaneously, including if the input protein sequence is an ARG, and if so, what antibiotic family it is resistant to, what resistant mechanism the ARG takes, and if the ARG is an intrinsic one or acquired one. In addition, if the predicted antibiotic family is beta-lactamase, HMD-ARG further predicts the subclass of beta-lactamase that the ARG is resistant to. Comprehensive experiments, including cross-fold validation, third-party dataset validation in human gut microbiota, wet-experimental functional validation, and structural investigation of predicted conserved sites, demonstrate not only the superior performance of our method over the state-of-art methods, but also the effectiveness and robustness of the proposed method. Conclusions We propose a hierarchical multi-task method, HMD-ARG, which is based on deep learning and can provide detailed annotations of ARGs from three important aspects: resistant antibiotic class, resistant mechanism, and gene mobility. We believe that HMD-ARG can serve as a powerful tool to identify antibiotic resistance genes and, therefore mitigate their global threat. Our method and the constructed database are available at http://www.cbrc.kaust.edu.sa/HMDARG/.


2020 ◽  
Vol 53 ◽  
pp. 35-43 ◽  
Author(s):  
Ross S McInnes ◽  
Gregory E McCallum ◽  
Lisa E Lamberte ◽  
Willem van Schaik

2016 ◽  
Vol 8 (5) ◽  
pp. 886-895 ◽  
Author(s):  
Nicolás Rascovan ◽  
Amar Telke ◽  
Didier Raoult ◽  
Jean Marc Rolain ◽  
Christelle Desnues

2012 ◽  
Vol 60 (2) ◽  
pp. 189-197 ◽  
Author(s):  
Osman Tel ◽  
Özkan Aslantaş ◽  
Oktay Keskin ◽  
Ebru Yilmaz ◽  
Cemil Demir

In this study,Staphylococcus aureusstrains (n = 110) isolated from seven ewe flocks in Sanliurfa, Turkey were screened for antibiotic resistance and biofilmforming ability as well as for genes associated with antibiotic resistance and biofilm-forming ability. All isolates were found to be susceptible to oxacillin, gentamicin, clindamycin, cefoxitin, tetracycline, vancomycin, amoxicillin-clavulanic acid, ciprofloxacin and sulphamethoxazole-trimethoprim. The percent proportions of strains resistant to penicillin G, ampicillin and erythromycin were 27.2% (n = 30), 25.4% (n = 28) and 6.3% (n = 7), respectively. Regarding the antibiotic resistance genes, 32 (29%) isolates carried theblaZ and 8 (7.2%) theermC gene. Other resistance genes were not detected in the isolates. All isolates showed biofilm-forming ability on Congo red agar (CRA), while 108 (98.18%) and 101 (91.81%) of them were identified as biofilm producers by the use of standard tube (ST) and microplate (MP) methods, respectively. All isolates carried theicaA andicaD genes but none of them harboured thebapgene. The results demonstrated thatS. aureusisolates from gangrenous mastitis were mainly resistant to penicillins (which are susceptible to the staphylococcal beta-lactamase enzyme), and less frequently to erythromycin. Furthermore, all of theS. aureusisolates produced biofilm which was considered a potential virulence factor in the pathogenesis of staphylococcal mastitis.


2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Natalia B. Naumova ◽  
Helen N. Ruchko ◽  
Oleg A. Savenkov ◽  
Valentina I. Pleshakova

The aim of the study. The aim of the study was to review publication about microbiome of chicken manure, chicken manure compost, as well as soil and crop microbiome after compost addition to soil as a fertilizer. Methodology. A search in the bibliographical data bases PubMed and elibrary.ru was performed using the keywords pertaining to the topic of the article. Main results. The results about the chicken manure microbiome, obtained by high throughput sequencing, showed that the chicken gut microbiome is dominated by bacteria of the Firmicutes and Bacteroidetes phyla; some regional chicken populations were found to have Clostridium, Lactobacillus, Eubacterium, Bacteroides, Escherichia coli, Prevotella, Selenomonas, Streptococcus, Megasphaera, Fusobacterium и Bifidobacterium as the main representatives of the gut microbiome. However, chicken manure can contain bacteria with antibiotic resistance genes, as antibiotics are increasingly used in the poultry industry to stimulate production. In general manure composting can be regarded as environmentally safe method for transforming various organic wastes into organic fertilizers. As increasing output of the poultry industry, which inevitably includes manure, increased the interest to its composting, and recent years have seen unprecedented number of research, dealing with various details of manure composting, such as duration, hydrothermal conditions, added bulking materials, microbiological preparations, abundance of the antibiotic resistance genes, and so on. However, the studies of soil and crop microbiome after soil fertilization with chicken manure compost have so far been rather scarce, resulting in ambiguous conclusions, i.e. about positive or no effect of the compost addition. The effect is determined by species, breed, age, rearing and manure composting technology, as well as by crop and its cultivar, agricultural practices and soil specifics. Conclusions. Chicken manure contains taxonomically diverse microbiome that can be changed during composting. Microbiota of chicken manure and its compost with their great microbial species richness can contain bacteria, carrying antibiotic resistance genes. Dispersal of such components of the compost resistome in environment via compost addition to agricultural soils should be regarded as a growing biological hazard, threatening the efficient use of antibiotics for treating bacterial infections in in veterinary and medicine. Therefore increasing poultry production urges for assessing the risks and evaluating the scope of the threat, as well as estimating and establishing permissible limits of pathomicrobiotic load of the poultry litter manure and compost, using up-to-date metagenomic techniques. The greatest concern is about spreading antibiotic resistance genes into the marketable crop components, consumed raw; consequently, alongside with studying microbiota of the compost-receiving agricultural soil as a source of dust, microbiome research should be also focused crop phytobiome where crops are produced under addition of composts, obtained with manure of the antibiotic-treated poultry during industrial production.


PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e2928 ◽  
Author(s):  
Graham Rose ◽  
Alexander G. Shaw ◽  
Kathleen Sim ◽  
David J. Wooldridge ◽  
Ming-Shi Li ◽  
...  

Background Few studies have investigated the gut microbiome of infants, fewer still preterm infants. In this study we sought to quantify and interrogate the resistome within a cohort of premature infants using shotgun metagenomic sequencing. We describe the gut microbiomes from preterm but healthy infants, characterising the taxonomic diversity identified and frequency of antibiotic resistance genes detected. Results Dominant clinically important species identified within the microbiomes included C. perfringens, K. pneumoniae and members of the Staphylococci and Enterobacter genera. Screening at the gene level we identified an average of 13 antimicrobial resistance genes per preterm infant, ranging across eight different antibiotic classes, including aminoglycosides and fluoroquinolones. Some antibiotic resistance genes were associated with clinically relevant bacteria, including the identification of mecA and high levels of Staphylococci within some infants. We were able to demonstrate that in a third of the infants the S. aureus identified was unrelated using MLST or metagenome assembly, but low abundance prevented such analysis within the remaining samples. Conclusions We found that the healthy preterm infant gut microbiomes in this study harboured a significant diversity of antibiotic resistance genes. This broad picture of resistances and the wider taxonomic diversity identified raises further caution to the use of antibiotics without consideration of the resident microbial communities.


2018 ◽  
Vol 10 (425) ◽  
pp. eaar7519
Author(s):  
Stephanie A. Christenson

The effect of antibiotic resistance genes on the gut microbiome is examined in preterm infants before and after antibiotic administration.


2019 ◽  
Vol 71 (2) ◽  
pp. 419-421
Author(s):  
Quentin Le Bastard ◽  
Pajau Vangay ◽  
Eric Batard ◽  
Dan Knights ◽  
Emmanuel Montassier

Abstract Little is known about the effect of human migration on gut microbiome antibiotic resistance gene (ARG) carriage. Using deep shotgun stool metagenomics analysis, we found a rapid increase in gut microbiome ARG richness and abundance in women from 2 independent ethnic groups relocating from Thailand to the United States.


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