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

Study information

Needs review

study design

randomized controlled trial

Citation

PMID PubMed identifier for scientific articles.

25487798

DOI Digital object identifier for electronic documents.

10.1128/AAC.04506-14

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 2

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Curated date: 2022/01/13

Curator: Mmarin

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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

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.

Significance threshold p-value or FDR threshold used for differential abundance testing (if any): 0.05

Alpha Diversity

Chao1 Abundance-based estimator of species richness: decreased

Signature 1

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Curated date: 2022/01/13

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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 Control	Links
Bifidobacterium adolescentis
Bifidobacterium dentium
Bifidobacterium sp.
Enterobacteriaceae bacterium
Sutterella parvirubra
Sutterella wadsworthensis

Revision editor(s): Mmarin

Signature 2

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Mark reviewed

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Curated date: 2022/01/13

Curator: Mmarin

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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 Control	Links
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