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Status |
Public on Aug 25, 2024 |
Title |
Differential effects of inosine monophosphate dehydrogenase (IMPDH/GuaB) inhibition in Acinetobacter baumannii and Escherichia coli |
Organisms |
Acinetobacter baumannii; Escherichia coli |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
Inosine 5’-monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in the de novo guanine biosynthesis and is conserved from humans to bacteria, where it is called GuaB. We developed a series of potent inhibitors that selectively target GuaB over its human homolog. Here we show that these GuaB inhibitors are bactericidal, generate phenotypic signatures that are distinct from other antibiotics, and elicit different time-kill kinetics and regulatory responses in two important gram-negative pathogens: Acinetobacter baumannii and Escherichia coli. Specifically, the GuaB inhibitor G6 rapidly kills A. baumannii but only kills E. coli after 24 hours. After exposure to G6, the expression of genes involved in purine biosynthesis and stress responses change in opposite directions while siderophore biosynthesis is downregulated in both species. Our results suggest that different species respond to GuaB inhibition using distinct regulatory programs, and possibly explain the different bactericidal kinetics upon GuaB inhibition. The comparison highlights opportunities for developing GuaB inhibitors as novel antibiotics.
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Overall design |
In this study, we examined the transcriptional responses to GuaB-specific inhibitors in A. baumannii and E. coli.
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Contributor(s) |
Peng Y, Skippington E |
Citation missing |
Has this study been published? Please login to update or notify GEO. |
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Submission date |
Aug 20, 2024 |
Last update date |
Aug 25, 2024 |
Contact name |
Yutian Peng |
Organization name |
Genentech Inc.
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Street address |
340 Point San Bruno
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City |
South San Francisco |
State/province |
CA |
ZIP/Postal code |
94080 |
Country |
USA |
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Platforms (2) |
GPL21433 |
Illumina HiSeq 4000 (Escherichia coli) |
GPL22143 |
Illumina HiSeq 4000 (Acinetobacter baumannii) |
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Samples (24)
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GSM8473780 |
ID12167962, Ecoli, No Drug, 1h |
GSM8473781 |
ID12167963, Ecoli, No Drug, 1h |
GSM8473782 |
ID12167964, Ecoli, No Drug, 1h |
GSM8473783 |
ID12167965, Ecoli, GuaBi, 1h |
GSM8473784 |
ID12167966, Ecoli, GuaBi, 1h |
GSM8473785 |
ID12167967, Ecoli, GuaBi, 1h |
GSM8473786 |
ID12167968, Ecoli, Cipro, 1h |
GSM8473787 |
ID12167969, Ecoli, Cipro, 1h |
GSM8473788 |
ID12167970, Ecoli, Cipro, 1h |
GSM8473789 |
ID12167906, Abaumannii, No Drug, 0h |
GSM8473790 |
ID12167907, Abaumannii, No Drug, 0h |
GSM8473791 |
ID12167908, Abaumannii, No Drug, 0h |
GSM8473792 |
ID12167909, Abaumannii, No Drug, 1h |
GSM8473793 |
ID12167910, Abaumannii, No Drug, 1h |
GSM8473794 |
ID12167911, Abaumannii, No Drug, 1h |
GSM8473795 |
ID12167912, Abaumannii, GuaBi, 1h |
GSM8473796 |
ID12167913, Abaumannii, GuaBi, 1h |
GSM8473797 |
ID12167914, Abaumannii, GuaBi, 1h |
GSM8473798 |
ID12167915, Abaumannii, Cipro, 1h |
GSM8473799 |
ID12167916, Abaumannii, Cipro, 1h |
GSM8473800 |
ID12167917, Abaumannii, Cipro, 1h |
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Relations |
BioProject |
PRJNA1150140 |
Supplementary file |
Size |
Download |
File type/resource |
GSE275261_Abaumannii_counts.txt.gz |
97.5 Kb |
(ftp)(http) |
TXT |
GSE275261_Abaumannii_metadata_genes.txt.gz |
58.4 Kb |
(ftp)(http) |
TXT |
GSE275261_Abaumannii_metadata_samples.txt.gz |
159 b |
(ftp)(http) |
TXT |
GSE275261_Ecoli_counts.txt.gz |
109.4 Kb |
(ftp)(http) |
TXT |
GSE275261_Ecoli_metadata_genes.txt.gz |
84.7 Kb |
(ftp)(http) |
TXT |
GSE275261_Ecoli_metadata_samples.txt.gz |
155 b |
(ftp)(http) |
TXT |
SRA Run Selector |
Raw data are available in SRA |
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