{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T22:35:39Z","timestamp":1789598139858,"version":"build-2803163510"},"reference-count":24,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2017,12,1]],"date-time":"2017-12-01T00:00:00Z","timestamp":1512086400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R21AI123747"],"award-info":[{"award-number":["R21AI123747"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI104895"],"award-info":[{"award-number":["R01AI104895"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2017,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    FosA proteins confer fosfomycin resistance to Gram-negative pathogens via glutathione-mediated modification of the antibiotic. In this study, we assessed whether inhibition of FosA by sodium phosphonoformate (PPF) (foscarnet), a clinically approved antiviral agent, would reverse fosfomycin resistance in representative Gram-negative pathogens. The inhibitory activity of PPF against purified recombinant FosA from\n                    <jats:named-content content-type=\"genus-species\">Escherichia coli<\/jats:named-content>\n                    (FosA3),\n                    <jats:named-content content-type=\"genus-species\">Klebsiella pneumoniae<\/jats:named-content>\n                    (FosA\n                    <jats:sup>KP<\/jats:sup>\n                    ),\n                    <jats:named-content content-type=\"genus-species\">Enterobacter cloacae<\/jats:named-content>\n                    (FosA\n                    <jats:sup>EC<\/jats:sup>\n                    ), and\n                    <jats:named-content content-type=\"genus-species\">Pseudomonas aeruginosa<\/jats:named-content>\n                    (FosA\n                    <jats:sup>PA<\/jats:sup>\n                    ) was determined by steady-state kinetic measurements. The antibacterial activity of PPF against FosA in clinical strains of these species was evaluated by susceptibility testing and time-kill assays. PPF increased the Michaelis constant (\n                    <jats:italic>\n                      K\n                      <jats:sub>m<\/jats:sub>\n                    <\/jats:italic>\n                    ) for fosfomycin in a dose-dependent manner, without affecting the maximum rate (\n                    <jats:italic>V<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    ) of the reaction, for all four FosA enzymes tested, indicating a competitive mechanism of inhibition. Inhibitory constant (\n                    <jats:italic>\n                      K\n                      <jats:sub>i<\/jats:sub>\n                    <\/jats:italic>\n                    ) values were 22.6, 35.8, 24.4, and 56.3 \u03bcM for FosA\n                    <jats:sup>KP<\/jats:sup>\n                    , FosA\n                    <jats:sup>EC<\/jats:sup>\n                    , FosA\n                    <jats:sup>PA<\/jats:sup>\n                    , and FosA3, respectively. Addition of clinically achievable concentrations of PPF (\u223c667 \u03bcM) reduced the fosfomycin MICs by \u22654-fold among 52% of the\n                    <jats:named-content content-type=\"genus-species\">K. pneumoniae<\/jats:named-content>\n                    ,\n                    <jats:named-content content-type=\"genus-species\">E. cloacae<\/jats:named-content>\n                    , and\n                    <jats:named-content content-type=\"genus-species\">P. aeruginosa<\/jats:named-content>\n                    clinical strains tested and led to a bacteriostatic or bactericidal effect in time-kill assays among representative strains. PPF inhibits FosA activity across Gram-negative species and can potentiate fosfomycin activity against the majority of strains with chromosomally encoded\n                    <jats:italic>fosA<\/jats:italic>\n                    . These data suggest that PPF may be repurposed as an adjuvant for fosfomycin to treat infections caused by some FosA-producing, multidrug-resistant, Gram-negative pathogens.\n                  <\/jats:p>","DOI":"10.1128\/aac.01424-17","type":"journal-article","created":{"date-parts":[[2017,10,9]],"date-time":"2017-10-09T20:50:18Z","timestamp":1507582218000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":27,"title":["Inhibition of Fosfomycin Resistance Protein FosA by Phosphonoformate (Foscarnet) in Multidrug-Resistant Gram-Negative Pathogens"],"prefix":"10.1128","volume":"61","author":[{"given":"Ryota","family":"Ito","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam D.","family":"Tomich","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christi L.","family":"McElheny","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta T.","family":"Mettus","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Sluis-Cremer","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"},{"name":"Center for Innovative Antimicrobial Therapy, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Doi","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"},{"name":"Center for Innovative Antimicrobial Therapy, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"},{"name":"Department of Microbiology, Fujita Health University, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.166.3901.122"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciq257"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics2020217"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01834-09"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.062653-0"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2014.08.010"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/lam.12366"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkw177"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00749-17"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(09)70325-1"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2010.12.003"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(92)90329-A"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi048767h"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.01094-14"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-199448020-00007"},{"key":"e_1_3_3_17_2","volume-title":"M100-S27","author":"Clinical and Laboratory Standards Institute","year":"2017","unstructured":"Clinical and Laboratory Standards Institute. 2017. 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