Microbiota-derived lantibiotic restores resistance against vancomycin-resistant Enterococcus

Kim, Sohn G.; Becattini, Simone; Moody, Thomas U.; Shliaha, Pavel V.; Littmann, Eric R.; Seok, Ruth; Gjonbalaj, Mergim; Eaton, Vincent; Fontana, Emily; Amoretti, Luigi A.; Wright, Roberta J.; Caballero, Silvia; Wang, Zhong-Min; Jung, Hea Jin; Morjaria, Sejal; Leiner, Ingrid; Qin, Weige; Ramos, Rúben J.; Cross, Justin R.; Narushima, Seiko; Honda, Kenya; Peled, Jonathan U.; Hendrickson, Ronald C.; Taur, Ying; Brink, Marcel R.M. van den; Pamer, Eric G.

doi:10.1038/s41586-019-1501-z

Cited by 221 publications

(206 citation statements)

References 42 publications

Supporting

Mentioning

200

Contrasting

Unclassified

Order By: Relevance

“…Unusually this operon encodes 4 peptides, the first 3 being identical and exhibiting similarity to nisin U, and the fourth showing the highest divergence from nisin A. Most interestingly, a further example of a multi-peptide operon from Blautia producta has recently been described and shown to be important in resistance against vancomycin-resistant Enterococcus in an animal model 17 . The nisin P operon was previously identified in the genomes of two Streptococcus species 15 but its activity has not been reported before.…”

Section: Introductionmentioning

confidence: 99%

First evidence of production of the lantibiotic nisin P

García-Gutiérrez

O’Connor

Saalbach

et al. 2019

Preprint

View full text Add to dashboard Cite

15Nisin P is a natural nisin variant, the genetic determinants for which were previously identified 16 in the genomes of two Streptococcus species, albeit with no confirmed evidence of production. 17 Here we describe Streptococcus agalactiae DPC7040, a human fecal isolate, which exhibits 18 antimicrobial activity against a panel of gut and food isolates by virtue of producing nisin P. 19 Nisin P was purified, and its predicted structure was confirmed by nanoLC-MS/MS, with both 20 the fully modified peptide and a variant without rings B and E being identified. Additionally, 21 we compared its spectrum of inhibition and minimum inhibitory concentration (MIC) with that 22 of nisin A and its antimicrobial effect in a fecal fermentation in comparison with nisin A and 23 H. We found that its antimicrobial activity was less potent than nisin A and H, and we propose 24 a link between this reduced activity and the peptide structure. 25 26 Keywords: nisin, antimicrobial, structure-activity relationship, fecal microbiome, 27 Structurally, nisin is classified as a lantibiotic because it contains lanthionine (Lan), an unusual 36 amino acid formed by two alanine residues linked by a sulphur atom through their β-carbon 4 . 37Other unusual amino acids present in nisin are dehydroalanine (Dha), dehydrobutyrine (Dhb) 38 3 3 and β-methyl-lanthionine 4 . Nisin activity and stability are closely related to its structure and 39 can be altered by pH changes. Increasing pH results in decreasing activity as a consequence of 40 alterations in structure, therefore, nisin is more stable at lower pH. Nisin is heat-stable and also 41 exhibits high stability at low temperatures, which makes it suitable for freeze-storage 7 . 42Nisin has nine reported natural variants ( Figure 1, Table 1). Nisin A is the most studied nisin 43 as it was the first one purified 8 . Nisin Z is considered the first natural variant of nisin A; it 44 differs in the presence of an asparagine amino acid in position 27 instead of a histidine residue 45 9 . This substitution has very little effect on antimicrobial activity, thermal and pH stability 46 compared to nisin A, but affects the solubility of the molecule, with nisin Z being more soluble 47 at neutral pH 10 . A study of its distribution also revealed that nisin Z is more widespread than 48 nisin A 10 . Nisin F, produced by L. lactis isolated from a fish gut, also has asparagine and valine 49 in positions 21 and 30 11 . Nisin Q was identified in an environmental L. lactis isolate and differs 50 from nisin A due to the presence of valine, leucine, asparagine and valine in positions 15, 21, 51 27 and 30, respectively 12 . Nisin U and U2 were the first variants found to be produced by a 52 species other than L. lactis 13 ; they are produced by Streptococcus uberis strain 42, isolated 53 from bovine mammary secretions 14 , and differ to nisin A by nine and ten amino acids, 54 respectively. Nisin H, produced by Streptococcus hyointestinalis was the first variant isolated 55 from a mammalian gastrointestin...

show abstract

Section: Introductionmentioning

confidence: 99%

First evidence of production of the lantibiotic nisin P

García-Gutiérrez

O’Connor

Saalbach

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…This research adds to the evidence that lantibiotic production may be an important trait of gut bacteria [Hatziioanou et al, 2017]. Moreover, gut microbiota produces broad spectrum of antimicrobials [Garcia-Gutierrez et al, 2019], which can be included in the development of protection mechanisms against colonization by pathobionts and others random third-party bacteria [Kamada et al, 2013;Kim et al, 2019]. Likewise, tetracyclines antibiotic resistance genes were found within the Hadza hunters-gatherers population in Tanzania, which were not exposed to anthropogenic pressure in comparison to the residents of modern urban areas [Rampelli et al, 2015].…”

Section: Discussionmentioning

confidence: 71%

Gut microbiota alterations due to fecal transplant

Olekhnovich

Ivanov

Ulyantsev

et al. 2020

Preprint

View full text Add to dashboard Cite

BackgroundFecal microbiota transplantation (FMT) is currently used to treat recurrent clostridial colitis and other diseases. However, neither the therapeutic mechanism of the FMT nor the mechanism that allows the donor bacteria to colonize the intestine of the recipient has yet been described. Moreover, FMT is a great model for studying the ecology of host-associated microbial communities. This creates the need for experimentation with approaches to metagenomic data analysis which may be useful to the interpretation of observed biological phenomena.MethodsHere the RECAST (Recipient intestinE Colonisation AnalysiS Tool) computational approach is presented, which is based on the shotgun reads sorting process in accordance with their origin in recipient metagenome. Using the RECAST algorithm, taxonomic/functional annotation, and machine learning, the shotgun metagenomic data from three FMT studies including healthy volunteers, patients with clostridial colitis and metabolic syndrome were analyzed.ResultsAccording to the analysis results, the colonizing and remaining microbial diversity in the post-FMT recipient metagenomic samples is clearly separated from the non-colonizers and lost. It is well explained by higher relative abundance in donor/pre-FMT recipient, Human Microbiome project metagenomes, and taxonomy. Moreover, the colonizing and remaining microbes are associated with lantibiotic and tetracyclines resistance genes.ConclusionBased on obtained results, the previously proposed “core” human gut microbiome concept may be elaborated. The top microbes of gut microbiota form “cores”, which, moreover, are mutually integrable between humans. Also, we assume that redistribution of microbial diversity in post-FMT recipients’ metagenomes is due to competition of donor/recipient microbes and to host immunity. The associations of top gut microbes with lantibiotic/antibiotic resistance can be related to gut microbiota colonization resistance phenomena or anthropogenic impact.

show abstract

“…Certain B. producta strains produce lantibiotic that can inhibit colonization by Gram-positive pathogenic bacteria such as vancomycin-resistant Enterococcus faecium. 59 Identifying the capability of β-1, 3-OSs utilization by such species may further strengthen their use as potential probiotics.…”

Section: Discussionmentioning

confidence: 99%

Linear and branched β-Glucans degrading enzymes from versatile Bacteroides uniformis JCM 13288^T and their roles in cooperation with gut bacteria

et al. 2020

View full text Add to dashboard Cite

β-glucans are the dietary nutrients present in oats, barley, algae, and mushrooms. The macromolecules are well known for their immune-modulatory activity; however, how the human gut bacteria digest them is vaguely understood. In this study, Bacteroides uniformis JCM 13288 T was found to grow on laminarin, pustulan, and porphyran. We sequenced the genome of the strain, which was about 5.05 megabase pairs and contained 4868 protein-coding genes. On the basis of growth patterns of the bacterium, two putative polysaccharide utilization loci for β-glucans were identified from the genome, and associated four putative genes were cloned, expressed, purified, and characterized. Three glycoside hydrolases (GHs) that were endo-acting enzymes (BuGH16, BuGH30, and BuGH158), and one which was an exo-acting (BuGH3) enzyme. The BuGH3, BuGH16, and BuGH158 can cleave linear exo/endo-β-1-3 linkages while BuGH30 can digest endo-β-1-6 linkages. BuGH30 and BuGH158 were further explored for their roles in digesting β-glucans and generation of oligosaccharides, respectively. The BuGH30 predominately found to cleave long chain β-1-6 linked glucans, and obtained final product was gentiobiose. The BuGH158 used for producing oligosaccharides varying from degree of polymerization 2 to 7 from soluble curdlan. We demonstrated that these oligosaccharides can be utilized by gut bacteria, which either did not grow or poorly grew on laminarin. Thus, B. uniformis JCM 13288 T is not only capable of utilizing β-glucans but also shares these glycans with human gut bacteria for potentially maintaining the gut microbial homeostasis.

show abstract

Microbiota-derived lantibiotic restores resistance against vancomycin-resistant Enterococcus

Cited by 221 publications

References 42 publications

First evidence of production of the lantibiotic nisin P

First evidence of production of the lantibiotic nisin P

Gut microbiota alterations due to fecal transplant

Linear and branched β-Glucans degrading enzymes from versatile Bacteroides uniformis JCM 13288^T and their roles in cooperation with gut bacteria

Contact Info

Product

Resources

About

Microbiota-derived lantibiotic restores resistance against vancomycin-resistant Enterococcus

Cited by 221 publications

References 42 publications

First evidence of production of the lantibiotic nisin P

First evidence of production of the lantibiotic nisin P

Gut microbiota alterations due to fecal transplant

Linear and branched β-Glucans degrading enzymes from versatile Bacteroides uniformis JCM 13288T and their roles in cooperation with gut bacteria

Contact Info

Product

Resources

About

Linear and branched β-Glucans degrading enzymes from versatile Bacteroides uniformis JCM 13288^T and their roles in cooperation with gut bacteria