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Título: | The inactivation of enzymes belonging to the central carbon metabolism is a novel mechanism of developing antibiotic resistance |
Autor: | Gil-Gil, Teresa; Corona, Fernando; Martínez, José Luis; Bernardini, Alejandra | Palabras clave: | Fosfomycin Antibiotic resistance Central carbon metabolism Embden-Meyerhof-Parnas pathway Stenotrophomonas Maltophilia |
Fecha de publicación: | 2020 | Editor: | American Society for Microbiology | Citación: | mSystems 5(3): e00282-20 (2020) | Resumen: | Fosfomycin is a bactericidal antibiotic, analogous to phosphoenolpyruvate, that exerts its activity by inhibiting the activity of MurA. This enzyme catalyzes the first step of peptidoglycan biosynthesis, the transfer of enolpyruvate from phosphoenolpyruvate to uridine-diphosphate-N-acetylglucosamine. Fosfomycin is increasingly being used, mainly for treating infections caused by Gram-negative multidrug-resistant bacteria. The mechanisms of mutational resistance to fosfomycin in Stenotrophomonas maltophilia, an opportunistic pathogen characterized by its low susceptibility to commonly used antibiotics, were studied in the current work. None of the mechanisms reported so far for other organisms, which include the production of fosfomycin-inactivating enzymes, target modification, induction of an alternative peptidoglycan biosynthesis pathway, and the impaired entry of the antibiotic, are involved in the acquisition of such resistance by this bacterial species. Instead, the unique cause of resistance in the mutants studied 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 inactivation nor transport of the antibiotic is involved. Transcriptomic analysis also showed that the mutants did not present changes in the expression level of putative alternative peptidoglycan biosynthesis pathway genes or any related enzyme. Finally, the mutants did not present an increased phosphoenolpyruvate concentration that might compete with fosfomycin for its binding to MurA. On the basis of these results, we describe a completely novel mechanism of antibiotic resistance based on mutations of genes encoding metabolic enzymes. | Descripción: | © 2020 Gil-Gil et al. | Versión del editor: | http://dx.doi.org/10.1128/mSystems.00282-20 | URI: | http://hdl.handle.net/10261/229971 | DOI: | 10.1128/mSystems.00282-20 | Identificadores: | doi: 10.1128/mSystems.00282-20 e-issn: 2379-5077 |
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