Microbiome changes in healthy volunteers treated with GSK1322322, a novel antibiotic targeting bacterial peptide deformylase

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Needs review
Citation
PMID PubMed identifier for scientific articles.
DOI Digital object identifier for electronic documents.
URI
Authors
Arat S, Spivak A, Van Horn S, Thomas E, Traini C, Sathe G, Livi GP, Ingraham K, Jones L, Aubart K, Holmes DJ, Naderer O, Brown JR
Journal
Antimicrobial agents and chemotherapy
Year
2015
GSK1322322 is a novel antibacterial agent under development, and it has known antibacterial activities against multidrug-resistant respiratory and skin pathogens through its inhibition of the bacterial peptide deformylase. Here, we used next-generation sequencing (NGS) of the bacterial 16S rRNA genes from stool samples collected from 61 healthy volunteers at the predosing and end-of-study time points to determine the effects of GSK1322322 on the gastrointestinal (GI) microbiota in a phase I, randomized, double-blind, and placebo-controlled study. GSK1322322 was administered either intravenously (i.v.) only or in an oral-i.v. combination in single- and repeat-dose-escalation infusions. Analysis of the 16S rRNA sequence data found no significant changes in the relative abundances of GI operational taxonomic units (OTUs) between the prestudy and end-of-study samples for either the placebo- or i.v.-only-treated subjects. However, oral-i.v. treatment resulted in significant decreases in some bacterial taxa, the Firmicutes and Bacteroidales, and increases in others, the Betaproteobacteria, Gammaproteobacteria, and Bifidobacteriaceae. Microbiome diversity plots clearly differentiated the end-of-study oral-i.v.-dosed samples from all others collected. The changes in genome function as inferred from species composition suggest an increase in bacterial transporter and xenobiotic metabolism pathways in these samples. A phylogenetic analysis of the peptide deformylase protein sequences collected from the published genomes of clinical isolates previously tested for GSK1322322 in vitro susceptibility and GI bacterial reference genomes suggests that antibiotic target homology is one of several factors that influences the response of GI microbiota to this antibiotic. Our study shows that dosing regimen and target class are important factors when considering the impact of antibiotic usage on GI microbiota. (This clinical trial was registered at the GlaxoSmithKline Clinical Study Register under study identifier PDF 113376.).

Experiment 1


Needs review

Curated date: 2021/11/04

Curator: Mmarin

Revision editor(s): WikiWorks, LGeistlinger, Mmarin, Aiyshaaaa, Victoria

Subjects

Location of subjects
United States of America
Host species Species from which microbiome was sampled. Contact us to have more species added.
Homo sapiens
Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology
Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces,feces
Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
Antimicrobial agent antibiotic,antibiotics,Antibiotika,Antibiotikum,antibiotique,antimicrobial,antimicrobial agents,microbicide,microbicides,Antimicrobial agent,antimicrobial agent
Group 0 name Corresponds to the control (unexposed) group for case-control studies
received oral-i.v.-administered GSK1322322 (prestudy)
Group 1 name Corresponds to the case (exposed) group for case-control studies
received oral-i.v.-administered GSK1322322 (end-of-study)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
received oral-i.v.-administered GSK1322322
Group 0 sample size Number of subjects in the control (unexposed) group
38
Group 1 sample size Number of subjects in the case (exposed) group
38

Lab analysis

Sequencing type
16S
16S variable region One or more hypervariable region(s) of the bacterial 16S gene
V4
Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
Illumina

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).
relative abundances
Statistical test
ANOVA
Significance threshold p-value or FDR threshold used for differential abundance testing (if any)
0.05
MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?
Yes

Alpha Diversity

Chao1 Abundance-based estimator of species richness
decreased

Signature 1

Reviewed Marked as Reviewed by Atrayees on 2023-7-27

Curated date: 2021/11/18

Curator: Mmarin

Revision editor(s): Mmarin

Source: Table 2

Description: Significantly changed gut bacterial operational taxonomic units in subjects receiving oral-i.v.-administered GSK1322322 in prestudy versus end-of-study comparisons

Abundance in Group 1: increased abundance in received oral-i.v.-administered GSK1322322 (end-of-study)

NCBI Quality ControlLinks
Bifidobacterium
Bifidobacterium adolescentis
Bifidobacterium pseudolongum
Enterobacteriaceae
Lachnospiraceae
Sutterella

Revision editor(s): Mmarin

Signature 2

Reviewed Marked as Reviewed by Atrayees on 2023-7-27

Curated date: 2021/11/18

Curator: Mmarin

Revision editor(s): Mmarin, Atrayees

Source: Table 2

Description: Significantly changed gut bacterial operational taxonomic units in subjects receiving oral-i.v.-administered GSK1322322 in prestudy versus end-of-study comparisons

Abundance in Group 1: decreased abundance in received oral-i.v.-administered GSK1322322 (end-of-study)

NCBI Quality ControlLinks
Anaerostipes
Bacteroidales
Bacteroides uniformis
Blautia
Blautia obeum
Butyricimonas
Eubacteriales
Faecalibacterium
Faecalibacterium prausnitzii
Odoribacter
Oscillospiraceae
Parabacteroides distasonis
Barnesiellaceae

Revision editor(s): Mmarin, Atrayees

Signature 3

Needs review

Curated date: 2021/11/19

Curator: Mmarin

Revision editor(s): Mmarin, Atrayees

Source: Figure 5

Description: Phylogenetic tree of peptide deformylase amino acid sequences for species of gastrointestinal (GI) microbiota detected in this study and bacterial pathogens with available MIC data for GSK1322322. Bacterial pathogens were classified as low susceptible (red) or high susceptible (green) according to an MIC cutoff of ≥ 8.0 μg/ml (see Materials and Methods). GI bacteria were classified by changes in oral-i.v. end-of-study compared to prestudy samples as having a statistically significant increase (blue) or decrease (orange) in the relative abundances, or as no change (black). The phylogenetic tree was reconstructed using the neighbor-joining method with the JTT option in the software MEGA6. Support for nodes in 1,000 bootstrap replicates is indicated by increased sizes as well as weighting to the red color spectrum of the circles at the nodes.

Abundance in Group 1: increased abundance in received oral-i.v.-administered GSK1322322 (end-of-study)

NCBI Quality ControlLinks
Bifidobacterium adolescentis
Bifidobacterium dentium
Bifidobacterium sp.
Enterobacteriaceae bacterium
Sutterella parvirubra
Sutterella wadsworthensis
Bacteroides thetaiotaomicron
Stenotrophomonas

Revision editor(s): Mmarin, Atrayees

Signature 4

incomplete

Curated date: 2021/11/19

Curator: Mmarin

Revision editor(s): Mmarin

Source: Figure 5

Description: Phylogenetic tree of peptide deformylase amino acid sequences for species of gastrointestinal (GI) microbiota detected in this study and bacterial pathogens with available MIC data for GSK1322322. Bacterial pathogens were classified as low susceptible (red) or high susceptible (green) according to an MIC cutoff of ≥ 8.0 μg/ml (see Materials and Methods). GI bacteria were classified by changes in oral-i.v. end-of-study compared to prestudy samples as having a statistically significant increase (blue) or decrease (orange) in the relative abundances, or as no change (black). The phylogenetic tree was reconstructed using the neighbor-joining method with the JTT option in the software MEGA6. Support for nodes in 1,000 bootstrap replicates is indicated by increased sizes as well as weighting to the red color spectrum of the circles at the nodes.

Abundance in Group 1: decreased abundance in received oral-i.v.-administered GSK1322322 (end-of-study)

NCBI Quality ControlLinks
Parabacteroides
Odoribacter
Segatella copri
Bacteroides uniformis
Odoribacter laneus
Oscillospiraceae bacterium
Faecalibacterium prausnitzii
[Ruminococcus] lactaris
Blautia hansenii
Ruminococcus sp.
unclassified Lachnospiraceae
Blautia hydrogenotrophica
Anaerostipes sp.
Ruminococcus bromii
Ruminococcus champanellensis
Mediterraneibacter gnavus

Revision editor(s): Mmarin

Experiment 2


Needs review

Curated date: 2022/01/13

Curator: Mmarin

Revision editor(s): Mmarin, WikiWorks, Aiyshaaaa, Victoria

Differences from previous experiment shown

Subjects

Lab analysis

Statistical Analysis

Statistical test
cluster analysis Statistical test: "cluster analysis" is not in the list (ANCOM, ANOSIM, ANOVA, Beta Binomial Regression, Chi-Square, Cox Proportional-Hazards Regression, Dunn's test, DESeq2, edgeR, Fisher's Exact Test, ...) of allowed values.
MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?
Not specified

Alpha Diversity

Chao1 Abundance-based estimator of species richness
decreased

Signature 1

Needs review

Curated date: 2022/01/13

Curator: Mmarin

Revision editor(s): Mmarin

Source: Figure 5

Description: Phylogenetic tree of peptide deformylase amino acid sequences for species of gastrointestinal (GI) microbiota detected in this study and bacterial pathogens with available MIC data for GSK1322322. Bacterial pathogens were classified as low susceptible (red) or high susceptible (green) according to an MIC cutoff of ≥ 8.0 μg/ml (see Materials and Methods). GI bacteria were classified by changes in oral-i.v. end-of-study compared to prestudy samples as having a statistically significant increase (blue) or decrease (orange) in the relative abundances, or as no change (black). The phylogenetic tree was reconstructed using the neighbor-joining method with the JTT option in the software MEGA6. Support for nodes in 1,000 bootstrap replicates is indicated by increased sizes as well as weighting to the red color spectrum of the circles at the nodes.

Abundance in Group 1: increased abundance in received oral-i.v.-administered GSK1322322 (end-of-study)

NCBI Quality ControlLinks
Bifidobacterium adolescentis
Bifidobacterium dentium
Bifidobacterium sp.
Enterobacteriaceae bacterium
Sutterella parvirubra
Sutterella wadsworthensis

Revision editor(s): Mmarin

Signature 2

Needs review

Curated date: 2022/01/13

Curator: Mmarin

Revision editor(s): Mmarin

Source: Figure 5

Description: Phylogenetic tree of peptide deformylase amino acid sequences for species of gastrointestinal (GI) microbiota detected in this study and bacterial pathogens with available MIC data for GSK1322322. Bacterial pathogens were classified as low susceptible (red) or high susceptible (green) according to an MIC cutoff of ≥ 8.0 μg/ml (see Materials and Methods). GI bacteria were classified by changes in oral-i.v. end-of-study compared to prestudy samples as having a statistically significant increase (blue) or decrease (orange) in the relative abundances, or as no change (black). The phylogenetic tree was reconstructed using the neighbor-joining method with the JTT option in the software MEGA6. Support for nodes in 1,000 bootstrap replicates is indicated by increased sizes as well as weighting to the red color spectrum of the circles at the nodes.

Abundance in Group 1: decreased abundance in received oral-i.v.-administered GSK1322322 (end-of-study)

NCBI Quality ControlLinks
Parabacteroides
Odoribacter
Segatella copri
Bacteroides uniformis
Odoribacter laneus
Oscillospiraceae bacterium
Faecalibacterium prausnitzii
[Ruminococcus] lactaris
Blautia hansenii
Ruminococcus sp.
unclassified Lachnospiraceae
Blautia hydrogenotrophica
Anaerostipes sp.
Ruminococcus bromii
Ruminococcus champanellensis
Mediterraneibacter gnavus

Revision editor(s): Mmarin