The absolute configuration of active and inactive fosfomycin

Perales, A.; Martı́nez-Ripoll, M.; Fayos, J.; Carstenn-Lichterfelde, C. von; Fernandez, M.

doi:10.1107/s056774088200990x

Cited by 7 publications

(4 citation statements)

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“…It has a broad spectrum of antibiotic activity in Gramnegative and Gram-positive bacteria by its irreversible inhibition of the UDP-N-acetylglucosamine-3-enolpyruvyl transferase (MurA) enzyme, which catalyzes the first step of the peptidoglycan biosynthesis (3). With a negatively charged phosphonic acid group, fosfomycin resembles the physiological substrate phosphoenolpyruvate and competitively inhibits its binding to the active site of MurA (4,5). At the physiological pH of 7.4, fosfomycin is singly negatively charged (6), and previous investigation has shown that this monoanionic form of fosfomycin is biologically active (4,5).…”

Section: Introductionmentioning

confidence: 99%

“…With a negatively charged phosphonic acid group, fosfomycin resembles the physiological substrate phosphoenolpyruvate and competitively inhibits its binding to the active site of MurA (4,5). At the physiological pH of 7.4, fosfomycin is singly negatively charged (6), and previous investigation has shown that this monoanionic form of fosfomycin is biologically active (4,5).…”

Section: Introductionmentioning

confidence: 99%

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Fosfomycin Permeation through the Outer Membrane Porin OmpF

Golla

Sans-Serramitjana

Pothula

et al. 2019

Biophysical Journal

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Fosfomycin is a frequently prescribed drug in the treatment of acute urinary tract infections. It enters the bacterial cytoplasm and inhibits the biosynthesis of peptidoglycans by targeting the MurA enzyme. Despite extensive pharmacological studies and clinical use, the permeability of fosfomycin across the bacterial outer membrane is largely unexplored. Here, we investigate the fosfomycin permeability across the outer membrane of Gram-negative bacteria by electrophysiology experiments as well as by all-atom molecular dynamics simulations including free-energy and applied-field techniques. Notably, in an electrophysiological zero-current assay as well as in the molecular simulations, we found that fosfomycin can rapidly permeate the abundant Escherichia coli porin OmpF. Furthermore, two triple mutants in the constriction region of the porin have been investigated. The permeation rates through these mutants are slightly lower than that of the wild type but fosfomycin can still permeate. Altogether, this work unravels molecular details of fosfomycin permeation through the outer membrane porin OmpF of E. coli and moreover provides hints for understanding the translocation of phosphonic acid antibiotics through other outer membrane pores.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fosfomycin Permeation through the Outer Membrane Porin OmpF

Golla

Sans-Serramitjana

Pothula

et al. 2019

Biophysical Journal

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“…Fosfomycin (18) is not currently used in the treatment of pneumococcal infections, but in this era of multidrug resistance, studies of this antibiotic may be valuable to inform decisions on future antibiotic use (19). Fosfomycin is a drug of particular interest for its synergy with benzylpenicillin, by decreasing the production of penicillin-binding proteins.…”

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confidence: 99%

Heteroresistance to Fosfomycin Is Predominant in Streptococcus pneumoniae and Depends on the murA1 Gene

Engel

Gutiérrez-Fernández

Flückiger

et al. 2013

Antimicrob Agents Chemother

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dFosfomycin targets the first step of peptidoglycan biosynthesis in Streptococcus pneumoniae catalyzed by UDP-N-acetylglucosamine enolpyruvyltransferase (MurA1). We investigated whether heteroresistance to fosfomycin occurs in S. pneumoniae. We found that of 11 strains tested, all but 1 (Hungary 19A ) displayed heteroresistance and that deletion of murA1 abolished heteroresistance. Hungary 19A differs from the other strains by a single amino acid substitution in MurA1 (Ala 364 Thr). To test whether this substitution is responsible for the lack of heteroresistance, it was introduced into strain D39. The heteroresistance phenotype of strain D39 was not changed. Furthermore, no relevant structural differences between the MurA1 crystal structures of heteroresistant strain D39 and nonheteroresistant strain Hungary 19A were found. Our results reveal that heteroresistance to fosfomycin is the predominant phenotype of S. pneumoniae and that MurA1 is required for heteroresistance to fosfomycin but is not the only factor involved. The findings provide a caveat for any future use of fosfomycin in the treatment of pneumococcal infections.

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“…74 Fosfomycin is present on the pharmaceutical market as the disodium, 75 calcium, 76 and tris(hydroxymethyl)ammonium salts. 77 The structure of the diester, monoester, disodium, calcium and phenethylammonium salts of fosfomycin have been studied by 1 78 Presently a number of methods are available for its synthesis and we selected the more attractive ones.…”

Section: Preparations Of Fosfomycinmentioning

confidence: 99%

The Syntheses and Properties of 1,2-Epoxyalkylphosphonates

Iorga¹,

Eymery²,

Savignac³

1999

Synthesis

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This review article deals with the methods of preparation of dialkyl 1,2-epoxyalkylphosphonates as well as synthetically useful reactions of this class of compounds. Four main routes to 1,2-epoxyalkylphosphonates are described, in which new developments adapted to each processes are given, including the choice of the leaving group, new cyclisation methods and stereocontrol induction. Thermal and acid-catalyzed rearrangements are also covered, and the use of the oxirane ring by nucleophilic opening is highlighted. Particular emphasis is placed on the synthetic approaches to antibiotic fosfomycin.

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The absolute configuration of active and inactive fosfomycin

Cited by 7 publications

References 1 publication

Fosfomycin Permeation through the Outer Membrane Porin OmpF

Fosfomycin Permeation through the Outer Membrane Porin OmpF

Heteroresistance to Fosfomycin Is Predominant in Streptococcus pneumoniae and Depends on the murA1 Gene

The Syntheses and Properties of 1,2-Epoxyalkylphosphonates

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