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| Status |
Public on May 11, 2020 |
| Title |
The inactivation of enzymes belonging to the central carbon metabolism, a novel mechanism of developing antibiotic resistance |
| Organism |
Stenotrophomonas maltophilia |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Fosfomycin is a bactericidal antibiotic, analogous to phosphoenolpyruvate (PEP) that exerts its activity by inhibiting the activity of MurA. This enzyme catalyzes the first step of peptidoglycan biosynthesis, the transfer of enolpyruvate from PEP to uridine- diphosphate-N-acetylglucosamine. Fosfomycin is increasingly used in the last years, mainly for treating infections caused by Gram-negative multidrug resistant bacteria as Stenotrophomonas maltophilia, an opportunistic pathogen characterized by its low susceptibility to antibiotics of common use. The mechanisms of mutational resistance to fosfomycin in Stenotrophomonas maltophilia were studied in the current work. None of the mechanisms so far described for other organisms, which include the production of fosfomycin inactivating enzymes, target modification, induction of alternative peptidoglycan biosynthesis pathway and the impaired entrance of the antibiotic, are involved in the acquisition of such resistance by this bacterial species. Rather the unique cause of resistance in the studied mutants is the mutational inactivation of different enzymes belonging to the Embden-Meyerhof-Parnas central metabolism pathway. The amount of intracellular fosfomycin accumulation did not change in any of these mutants showing that neither the inactivation nor the transport of the antibiotic were involved. Transcriptomic analysis also showed that the mutants did not present changes in the expression level of putative alternative peptidoglycan biosynthesis pathway genes neither any related enzyme. Finally, the mutants did not present an increased PEP concentration that might compete with fosfomycin for its binding to MurA. Based on these results, we describe a completely novel mechanism of antibiotic resistance based on the remodeling of S. maltophilia metabolism.
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| Overall design |
Stenotrophomonas maltophilia D457 and fosfomycin resistant mutants (FOS1, FOS4, FOS7 and FOS8) mRNA profiles measured by paired-end RNA-seq
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| Contributor(s) |
Gil-Gil T, Corona F, MartÃnez JL, Bernardini A |
| Citation(s) |
32487742 |
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| Submission date |
Dec 02, 2019 |
| Last update date |
Nov 03, 2021 |
| Contact name |
Juan Carlos Oliveros |
| Organization name |
CNB, CSIC
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| Street address |
Darwin 3
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| City |
Cantoblanco |
| State/province |
Madrid |
| ZIP/Postal code |
28049 |
| Country |
Spain |
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| Platforms (1) |
| GPL25680 |
Illumina HiSeq 2500 (Stenotrophomonas maltophilia) |
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| Samples (5)
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| Relations |
| BioProject |
PRJNA592991 |
| SRA |
SRP234424 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE141276_processed_data_RPKM.xls.gz |
161.8 Kb |
(ftp)(http) |
XLS |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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