Characterization of <i>fosA5</i>
, a new plasmid-mediated fosfomycin resistance gene in <i>Escherichia coli</i>

Ma, Yiming; Xu, Xiaogang; Guo, Qinglan; Wang, P.; Wang, W.; Wang, M.

doi:10.1111/lam.12366

Cited by 55 publications

(44 citation statements)

References 19 publications

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“…fosA is frequently identified in the E. coli and K. pneumoniae genomes 35,36 . The fosA5 gene is first found in E. coli in 2014 37 . In 2017, it was reported that all of 73 carbapenem-resistant K. pneumoniae isolates were positive for fosA5 in one Chinese area: Zhejiang Province 38 .…”

Section: Discussionmentioning

confidence: 99%

Molecular characterization of carbapenem-resistant Klebsiella pneumoniae isolates with focus on antimicrobial resistance

Zhang

Zhao

et al. 2019

Preprint

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19The enhancing incidence of carbapenem-resistant Klebsiella pneumoniae (CRKP)-mediated 20 infections in Mengchao Hepatobiliary Hospital of Fujian Medical University in 2017 is the 21 motivation behind this investigation to study gene phenotypes and resistance-associated genes of 22 emergence regarding the CRKP strains. In current study, seven inpatients are enrolled in the 23 hospital with complete treatments. The carbapenem-resistant K. pneumoniae whole genome is 24 sequenced using MiSeq short-read and Oxford Nanopore long-read sequencing technology. 25Prophages are identified to assess genetic diversity within CRKP genomes. The investigation 26 encompassed eight CRKP strains that collected from the patients enrolled as well as the 27 environment, which illustrate that blaKPC-2 is responsible for phenotypic resistance in six CRKP 28 strains that K. pneumoniae sequence type (ST11) is informed. The plasmid with IncR, ColRNAI 29 and pMLST type with IncF[F33:A-:B-] co-exist in all ST11 with KPC-2-producing CRKP 30 strains. Along with carbapenemases, all K. pneumoniae strains harbor two or three extended 31 spectrum β-lactamase (ESBL)-producing genes. fosA gene is detected amongst all the CRKP 32 strains. The single nucleotide polymorphisms (SNP) markers are indicated and validated among 33 all CRKP strains, providing valuable clues for distinguishing carbapenem-resistant strains from 34 conventional K. pneumoniae. In conclusion, ST11 is the main CRKP type, and blaKPC-2 is the 35 dominant carbapenemase gene harbored by clinical CRKP isolates from current investigations. 36

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Section: Discussionmentioning

confidence: 99%

Molecular characterization of carbapenem-resistant Klebsiella pneumoniae isolates with focus on antimicrobial resistance

Zhang

Zhao

et al. 2019

Preprint

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“…It catalyzes the reaction between glutathione and fosfomycin to an inactive adduct (102,(105)(106)(107). New subtypes, with similar structure, of the gene have been described (fosA2, fosA3, fosA4, and fosA5) (108)(109)(110). Cooccurrence in plasmids with bla CTX-M , bla NDM , bla KPC , bla OXA , bla CMY , bla AmpC , bla TEM , bla SHV , bla SFO-1 , gyrA, parC, parE, sul1, sul2, strA, strB, aac(6=)-Ib, aadA5, aphA6, tetA(A), mphA, floR, dfrA7, rmtB, and merA genes has been reported, conferring resistance to ␤-lactams, quinolones, aminoglycosides, macrolides, sulfonamides, and tetracyclines (75,80,(111)(112)(113)(114).…”

Section: Acquired Resistancementioning

confidence: 99%

Fosfomycin

et al. 2016

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SUMMARYThe treatment of bacterial infections suffers from two major problems: spread of multidrug-resistant (MDR) or extensively drug-resistant (XDR) pathogens and lack of development of new antibiotics active against such MDR and XDR bacteria. As a result, physicians have turned to older antibiotics, such as polymyxins, tetracyclines, and aminoglycosides. Lately, due to development of resistance to these agents, fosfomycin has gained attention, as it has remained active against both Gram-positive and Gram-negative MDR and XDR bacteria. New data of higher quality have become available, and several issues were clarified further. In this review, we summarize the available fosfomycin data regarding pharmacokinetic and pharmacodynamic properties, thein vitroactivity against susceptible and antibiotic-resistant bacteria, mechanisms of resistance and development of resistance during treatment, synergy and antagonism with other antibiotics, clinical effectiveness, and adverse events. Issues that need to be studied further are also discussed.

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“…By far the most widespread plasmid-borne fosA is fosA3, which has been reported to be present in up to 90% of fosfomycin-resistant extended-spectrum-␤-lactamase (ESBL)-producing E. coli isolates in China (8). Chromosomally encoded fosA from K. pneumoniae (fosA KP ) also represents a substantial risk to human health because it confers intrinsic reduced fosfomycin susceptibility in K. pneumoniae and can also serve as a reservoir for the nearly identical plasmid-borne genes fosA5 and fosA6 (9,10).…”

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confidence: 99%

Structure and Dynamics of FosA-Mediated Fosfomycin Resistance in Klebsiella pneumoniae and Escherichia coli

Klontz

Tomich

Günther

et al. 2017

Antimicrob Agents Chemother

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Fosfomycin exhibits broad-spectrum antibacterial activity and is being reevaluated for the treatment of extensively drug-resistant pathogens. Its activity in Gram-negative organisms, however, can be compromised by expression of FosA, a metal-dependent transferase that catalyzes the conjugation of glutathione to fosfomycin, rendering the antibiotic inactive. In this study, we solved the crystal structures of two of the most clinically relevant FosA enzymes: plasmid-encoded FosA3 from and chromosomally encoded FosA from (FosA). The structure, molecular dynamics, catalytic activity, and fosfomycin resistance of FosA3 and FosA were also compared to those of FosA from (FosA), for which prior crystal structures exist. TOP10 transformants expressing FosA3 and FosA conferred significantly greater fosfomycin resistance (MIC, >1,024 μg/ml) than those expressing FosA (MIC, 16 μg/ml), which could be explained in part by the higher catalytic efficiencies of the FosA3 and FosA enzymes. Interestingly, these differences in enzyme activity could not be attributed to structural differences at their active sites. Instead, molecular dynamics simulations and hydrogen-deuterium exchange experiments with FosA revealed dynamic interconnectivity between its active sites and a loop structure that extends from the active site of each monomer and traverses the dimer interface. This dimer interface loop is longer and more extended in FosA and FosA3 than in FosA, and kinetic analyses of FosA and FosA loop-swapped chimeric enzymes highlighted its importance in FosA activity. Collectively, these data yield novel insights into fosfomycin resistance that could be leveraged to develop new strategies to inhibit FosA and potentiate fosfomycin activity.

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Characterization of fosA5 , a new plasmid-mediated fosfomycin resistance gene in Escherichia coli

Cited by 55 publications

References 19 publications

Molecular characterization of carbapenem-resistant Klebsiella pneumoniae isolates with focus on antimicrobial resistance

Molecular characterization of carbapenem-resistant Klebsiella pneumoniae isolates with focus on antimicrobial resistance

Fosfomycin

Structure and Dynamics of FosA-Mediated Fosfomycin Resistance in Klebsiella pneumoniae and Escherichia coli

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