Bacterial infections caused by antibiotic-resistant isolates have become a major health problem in recent years, since they are very difficult to treat, leading to an increase in morbidity and mortality. Fosfomycin is a broad-spectrum bactericidal antibiotic that inhibits cell wall biosynthesis in both Gram-negative and Gram-positive bacteria. This antibiotic has a unique mechanism of action and inhibits the initial step in peptidoglycan biosynthesis by blocking the enzyme, MurA. Fosfomycin has been used successfully for the treatment of urinary tract infections for a long time, but the increased emergence of antibiotic resistance has made fosfomycin a suitable candidate for the treatment of infections caused by multidrug-resistant pathogens, especially in combination with other therapeutic partners. The acquisition of fosfomycin resistance could threaten the reintroduction of this antibiotic for the treatment of bacterial infection. Here, we analyse the mechanism of action and molecular mechanisms for the development of fosfomycin resistance, including the modification of the antibiotic target, reduced antibiotic uptake and antibiotic inactivation. In addition, we describe the role of each pathway in clinical isolates.
References
[1]
Nathan, C. Antibiotics at the crossroads. Nature 2004, 431, 899–902, doi:10.1038/431899a.
[2]
Livermore, D.M. Has the era of untreatable infections arrived? J. Antimicrob. Chemother. 2009, 64 (Suppl. 1), 29–36, doi:10.1093/jac/dkp255.
[3]
Falagas, M.E.; Grammatikos, A.P.; Michalopoulos, A. Potential of old-generation antibiotics to address current need for new antibiotics. Expert Rev. Anti. Infect. Ther. 2008, 6, 593–600.
[4]
Hendlin, D.; Stapley, E.O.; Jackson, M.; Wallick, H.; Miller, A.K.; Wolf, F.J.; Miller, T.W.; Chaiet, L.; Kahan, F.M.; Foltz, E.L.; et al. Phosphonomycin, a new antibiotic produced by strains of Streptomyces. Science 1969, 166, 122–123.
[5]
Kahan, F.M.; Kahan, J.S.; Cassidy, P.J.; Kropp, H. The mechanism of action of fosfomycin (phosphonomycin). Ann. NY Acad. Sci. 1974, 235, 364–386.
Schito, G.C. Why fosfomycin trometamol as first line therapy for uncomplicated UTI? Int. J. Antimicrob. Agents 2003, 22 (Suppl. 2), 79–83, doi:10.1016/S0924-8579(03)00231-0.
Barry, A.L.; Brown, S.D. Antibacterial spectrum of fosfomycin trometamol. J. Antimicrob. Chemother. 1995, 35, 228–230, doi:10.1093/jac/35.1.228.
[10]
Lu, C.L.; Liu, C.Y.; Huang, Y.T.; Liao, C.H.; Teng, L.J.; Turnidge, J.D.; Hsueh, P.R. Antimicrobial susceptibilities of commonly encountered bacterial isolates to fosfomycin determined by agar dilution and disk diffusion methods. Antimicrob. Agents Chemother. 2011, 55, 4295–4301, doi:10.1128/AAC.00349-11.
[11]
Falagas, M.E.; Kastoris, A.C.; Karageorgopoulos, D.E.; Rafailidis, P.I. Fosfomycin for the treatment of infections caused by multidrug-resistant non-fermenting gram-negative bacilli: A systematic review of microbiological, animal and clinical studies. Int. J. Antimicrob. Agents 2009, 34, 111–120, doi:10.1016/j.ijantimicag.2009.03.009.
[12]
Neuner, E.A.; Sekeres, J.; Hall, G.S.; van Duin, D. Experience with fosfomycin for treatment of urinary tract infections due to multidrug-resistant organisms. Antimicrob. Agents Chemother. 2012, 56, 5744–5748.
[13]
Falagas, M.E.; Kastoris, A.C.; Kapaskelis, A.M.; Karageorgopoulos, D.E. Fosfomycin for the treatment of multidrug-resistant, including extended-spectrum beta-lactamase producing, Enterobacteriaceae infections: A systematic review. Lancet Infect. Dis. 2010, 10, 43–50, doi:10.1016/S1473-3099(09)70325-1.
[14]
Brown, E.D.; Vivas, E.I.; Walsh, C.T.; Kolter, R. MurA (MurZ), the enzyme that catalyzes the first committed step in peptidoglycan biosynthesis, is essential in Escherichia coli. J. Bacteriol. 1995, 177, 4194–4197.
[15]
Marquardt, J.L.; Brown, E.D.; Lane, W.S.; Haley, T.M.; Ichikawa, Y.; Wong, C.H.; Walsh, C.T. Kinetics, stoichiometry, and identification of the reactive thiolate in the inactivation of UDP-GlcNAc enolpyruvoyl transferase by the antibiotic fosfomycin. Biochemistry 1994, 33, 10646–10651.
[16]
Skarzynski, T.; Mistry, A.; Wonacott, A.; Hutchinson, S.E.; Kelly, V.A.; Duncan, K. Structure of UDP-N-acetylglucosamine enolpyruvyl transferase, an enzyme essential for the synthesis of bacterial peptidoglycan, complexed with substrate UDP-N-acetylglucosamine and the drug fosfomycin. Structure 1996, 4, 1465–1474, doi:10.1016/S0969-2126(96)00153-0.
[17]
Kadner, R.J.; Winkler, H.H. Isolation and characterization of mutations affecting the transport of hexose phosphates in Escherichia coli. J. Bacteriol. 1973, 113, 895–900.
[18]
Tsuruoka, T.; Yamada, Y. Charactertization of spontaneous fosfomycin (phosphonomycin)-resistant cells of Escherichia coli B in vitro. J. Antibiot. (Tokyo) 1975, 28, 906–911, doi:10.7164/antibiotics.28.906.
[19]
Grimm, H. In vitro investigations with fosfomycin on Mueller-Hinton agar with and without glucose-6-phosphate. Infection 1979, 7, 256–259.
[20]
Castaneda-Garcia, A.; Rodriguez-Rojas, A.; Guelfo, J.R.; Blazquez, J. The glycerol-3-phosphate permease GlpT is the only fosfomycin transporter in Pseudomonas aeruginosa. J. Bacteriol. 2009, 191, 6968–6974, doi:10.1128/JB.00748-09.
[21]
Schweizer, H.P.; Po, C. Regulation of glycerol metabolism in Pseudomonas aeruginosa: Characterization of the glpR repressor gene. J. Bacteriol. 1996, 178, 5215–5221.
[22]
Scortti, M.; Lacharme-Lora, L.; Wagner, M.; Chico-Calero, I.; Losito, P.; Vazquez-Boland, J.A. Coexpression of virulence and fosfomycin susceptibility in Listeria: Molecular basis of an antimicrobial in vitro-in vivo paradox. Nat. Med. 2006, 12, 515–517, doi:10.1038/nm1396.
[23]
Chico-Calero, I.; Suarez, M.; Gonzalez-Zorn, B.; Scortti, M.; Slaghuis, J.; Goebel, W.; Vazquez-Boland, J.A. Hpt, a bacterial homolog of the microsomal glucose-6-phosphate translocase, mediates rapid intracellular proliferation in Listeria. Proc. Natl. Acad. Sci. USA 2002, 99, 431–436.
[24]
Lemieux, M.J.; Huang, Y.; Wang, D.N. Glycerol-3-phosphate transporter of Escherichia coli: Structure, function and regulation. Res. Microbiol. 2004, 155, 623–629, doi:10.1016/j.resmic.2004.05.016.
[25]
Huang, Y.; Lemieux, M.J.; Song, J.; Auer, M.; Wang, D.N. Structure and mechanism of the glycerol-3-phosphate transporter from Escherichia coli. Science 2003, 301, 616–620, doi:10.1126/science.1087619.
[26]
Lemieux, M.J.; Huang, Y.; Wang, D.N. The structural basis of substrate translocation by the Escherichia coli glycerol-3-phosphate transporter: A member of the major facilitator superfamily. Curr. Opin. Struct. Biol. 2004, 14, 405–412, doi:10.1016/j.sbi.2004.06.003.
[27]
Elvin, C.M.; Hardy, C.M.; Rosenberg, H. Pi exchange mediated by the glpt-dependent sn-glycerol-3-phosphate transport system in Escherichia coli. J. Bacteriol. 1985, 161, 1054–1058.
[28]
Hardisson, C.; Llaneza, J. The action of fosfomycin on the growth of Pseudomonas aeruginosa. Chemotherapy 1977, 23 (Suppl. 1), 37–44, doi:10.1159/000222024.
[29]
Lindgren, V. Mapping of a genetic locus that affects glycerol 3-phosphate transport in Bacillus subtilis. J. Bacteriol. 1978, 133, 667–670.
[30]
Santoro, A.; Cappello, A.R.; Madeo, M.; Martello, E.; Iacopetta, D.; Dolce, V. Interaction of fosfomycin with the glycerol 3-phosphate transporter of Escherichia coli. Biochim. Biophys. Acta 2011, 1810, 1323–1329, doi:10.1016/j.bbagen.2011.07.006.
[31]
Larson, T.J.; Ye, S.Z.; Weissenborn, D.L.; Hoffmann, H.J.; Schweizer, H. Purification and characterization of the repressor for the sn-glycerol 3-phosphate regulon of Escherichia coli K-12. J. Biol. Chem. 1987, 262, 15869–15874.
[32]
Yang, B.; Gerhardt, S.G.; Larson, T.J. Action at a distance for glp repressor control of glpTQ transcription in Escherichia coli K-12. Mol. Microbiol. 1997, 24, 511–521, doi:10.1046/j.1365-2958.1997.3651733.x.
[33]
Zeng, G.; Ye, S.; Larson, T.J. Repressor for the sn-glycerol 3-phosphate regulon of Escherichia coli K-12: Primary structure and identification of the DNA-binding domain. J. Bacteriol. 1996, 178, 7080–7089.
[34]
Kadner, R.J.; Shattuck-Eidens, D.M. Genetic control of the hexose phosphate transport system of Escherichia coli: Mapping of deletion and insertion mutations in the uhp region. J. Bacteriol. 1983, 155, 1052–1061.
[35]
Sonna, L.A.; Ambudkar, S.V.; Maloney, P.C. The mechanism of glucose 6-phosphate transport by Escherichia coli. J. Biol. Chem. 1988, 263, 6625–6630.
[36]
Eiglmeier, K.; Boos, W.; Cole, S.T. Nucleotide sequence and transcriptional startpoint of the glpT gene of Escherichia coli: Extensive sequence homology of the glycerol-3-phosphate transport protein with components of the hexose-6-phosphate transport system. Mol. Microbiol. 1987, 1, 251–258, doi:10.1111/j.1365-2958.1987.tb01931.x.
[37]
Ambudkar, S.V.; Anantharam, V.; Maloney, P.C. UhpT, the sugar phosphate antiporter of Escherichia coli, functions as a monomer. J. Biol. Chem. 1990, 265, 12287–12292.
[38]
Lloyd, A.D.; Kadner, R.J. Topology of the Escherichia coli uhpT sugar-phosphate transporter analyzed by using TnphoA fusions. J. Bacteriol. 1990, 172, 1688–1693.
[39]
Island, M.D.; Kadner, R.J. Interplay between the membrane-associated UhpB and UhpC regulatory proteins. J. Bacteriol. 1993, 175, 5028–5034.
[40]
Chen, Q.; Kadner, R.J. Effect of altered spacing between uhpT promoter elements on transcription activation. J. Bacteriol. 2000, 182, 4430–4436, doi:10.1128/JB.182.16.4430-4436.2000.
[41]
Dahl, J.L.; Wei, B.Y.; Kadner, R.J. Protein phosphorylation affects binding of the Escherichia coli transcription activator UhpA to the uhpT promoter. J. Biol. Chem. 1997, 272, 1910–1919.
[42]
Olekhnovich, I.N.; Kadner, R.J. Mutational scanning and affinity cleavage analysis of UhpA-binding sites in the Escherichia coli uhpT promoter. J. Bacteriol. 2002, 184, 2682–2691, doi:10.1128/JB.184.10.2682-2691.2002.
[43]
Alper, M.D.; Ames, B.N. Transport of antibiotics and metabolite analogs by systems under cyclic AMP control: Positive selection of Salmonella typhimurium cya and crp mutants. J. Bacteriol. 1978, 133, 149–157.
[44]
Cordaro, J.C.; Melton, T.; Stratis, J.P.; Atagun, M.; Gladding, C.; Hartman, P.E.; Roseman, S. Fosfomycin resistance: Selection method for internal and extended deletions of the phosphoenolpyruvate: Sugar phosphotransferase genes of Salmonella typhimurium. J. Bacteriol. 1976, 128, 785–793.
[45]
Sakamoto, Y.; Furukawa, S.; Ogihara, H.; Yamasaki, M. Fosmidomycin resistance in adenylate cyclase deficient (cya) mutants of Escherichia coli. Biosci. Biotechnol. Biochem. 2003, 67, 2030–2033, doi:10.1271/bbb.67.2030.
[46]
Tsuruoka, T.; Miyata, A.; Yamada, Y. Two kinds of mutants defective in multiple carbohydrate utilization isolated from in vitro fosfomycin-resistant strains of Escherichia coli K-12. J. Antibiot. (Tokyo) 1978, 31, 192–201, doi:10.7164/antibiotics.31.192.
[47]
Larson, T.J.; Cantwell, J.S.; van Loo-Bhattacharya, A.T. Interaction at a distance between multiple operators controls the adjacent, divergently transcribed glpTQ-glpACB operons of Escherichia coli K-12. J. Biol. Chem. 1992, 267, 6114–6121.
[48]
Merkel, T.J.; Dahl, J.L.; Ebright, R.H.; Kadner, R.J. Transcription activation at the Escherichia coli uhpT promoter by the catabolite gene activator protein. J. Bacteriol. 1995, 177, 1712–1718.
[49]
Olekhnovich, I.N.; Dahl, J.L.; Kadner, R.J. Separate contributions of UhpA and CAP to activation of transcription of the uhpT promoter of Escherichia coli. J. Mol. Biol. 1999, 292, 973–986, doi:10.1006/jmbi.1999.3127.
[50]
Kim, D.H.; Lees, W.J.; Kempsell, K.E.; Lane, W.S.; Duncan, K.; Walsh, C.T. Characterization of a Cys115 to Asp substitution in the Escherichia coli cell wall biosynthetic enzyme UDP-GlcNAc enolpyruvyl transferase (MurA) that confers resistance to inactivation by the antibiotic fosfomycin. Biochemistry 1996, 35, 4923–4928.
[51]
Brown, E.D.; Marquardt, J.L.; Lee, J.P.; Walsh, C.T.; Anderson, K.S. Detection and characterization of a phospholactoyl-enzyme adduct in the reaction catalyzed by UDP-N-acetylglucosamine enolpyruvoyl transferase, MurZ. Biochemistry 1994, 33, 10638–10645.
[52]
Ramilo, C.; Appleyard, R.J.; Wanke, C.; Krekel, F.; Amrhein, N.; Evans, J.N. Detection of the covalent intermediate of UDP-N-acetylglucosamine enolpyruvyl transferase by solution-state and time-resolved solid-state NMR spectroscopy. Biochemistry 1994, 33, 15071–15079.
[53]
Wanke, C.; Amrhein, N. Evidence that the reaction of the UDP-N-acetylglucosamine 1-carboxyvinyltransferase proceeds through the O-phosphothioketal of pyruvic acid bound to Cys115 of the enzyme. Eur. J. Biochem. 1993, 218, 861–870, doi:10.1111/j.1432-1033.1993.tb18442.x.
[54]
Eschenburg, S.; Priestman, M.; Schonbrunn, E. Evidence that the fosfomycin target Cys115 in UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) is essential for product release. J. Biol. Chem. 2005, 280, 3757–3763, doi:10.1074/jbc.M411325200.
[55]
De Smet, K.A.; Kempsell, K.E.; Gallagher, A.; Duncan, K.; Young, D.B. Alteration of a single amino acid residue reverses fosfomycin resistance of recombinant MurA from Mycobacterium tuberculosis. Microbiology 1999, 145, 3177–3184.
[56]
Jiang, S.; Gilpin, M.E.; Attia, M.; Ting, Y.L.; Berti, P.J. Lyme disease enolpyruvyl-udp-glcnac synthase: Fosfomycin-resistant MurA from Borrelia burgdorferi, a fosfomycin-sensitive mutant, and the catalytic role of the active site Asp. Biochemistry 2011, 50, 2205–2212, doi:10.1021/bi1017842.
[57]
McCoy, A.J.; Sandlin, R.C.; Maurelli, A.T. In vitro and in vivo functional activity of Chlamydia MurA, a UDP-N-acetylglucosamine enolpyruvyl transferase involved in peptidoglycan synthesis and fosfomycin resistance. J. Bacteriol. 2003, 185, 1218–1228, doi:10.1128/JB.185.4.1218-1228.2003.
[58]
Venkateswaran, P.S.; Wu, H.C. Isolation and characterization of a phosphonomycin-resistant mutant of Escherichia coli K-12. J. Bacteriol. 1972, 110, 935–944.
[59]
Takahata, S.; Ida, T.; Hiraishi, T.; Sakakibara, S.; Maebashi, K.; Terada, S.; Muratani, T.; Matsumoto, T.; Nakahama, C.; Tomono, K. Molecular mechanisms of fosfomycin resistance in clinical isolates of Escherichia coli. Int. J. Antimicrob. Agents 2010, 35, 333–337, doi:10.1016/j.ijantimicag.2009.11.011.
[60]
Marquardt, J.L.; Siegele, D.A.; Kolter, R.; Walsh, C.T. Cloning and sequencing of Escherichia coli MurZ and purification of its product, a UDP-N-acetylglucosamine enolpyruvyl transferase. J. Bacteriol. 1992, 174, 5748–5752.
[61]
Couce, A.; Briales, A.; Rodriguez-Rojas, A.; Costas, C.; Pascual, A.; Blazquez, J. Genomewide overexpression screen for fosfomycin resistance in Escherichia coli: MurA confers clinical resistance at low fitness cost. Antimicrob. Agents Chemother. 2012, 56, 2767–2769, doi:10.1128/AAC.06122-11.
[62]
Horii, T.; Kimura, T.; Sato, K.; Shibayama, K.; Ohta, M. Emergence of fosfomycin-resistant isolates of shiga-like toxin-producing Escherichia coli O26. Antimicrob. Agents Chemother. 1999, 43, 789–793.
[63]
Rigsby, R.E.; Fillgrove, K.L.; Beihoffer, L.A.; Armstrong, R.N. Fosfomycin resistance proteins: A nexus of glutathione transferases and epoxide hydrolases in a metalloenzyme superfamily. Meth. Enzymol. 2005, 401, 367–379.
[64]
Brown, D.W.; Schaab, M.R.; Birmingham, W.R.; Armstrong, R.N. Evolution of the antibiotic resistance protein, FosA, is linked to a catalytically promiscuous progenitor. Biochemistry 2009, 48, 1847–1849.
[65]
Armstrong, R.N. Mechanistic imperatives for the evolution of glutathione transferases. Curr. Opin. Chem. Biol. 1998, 2, 618–623, doi:10.1016/S1367-5931(98)80093-8.
[66]
Armstrong, R.N. Mechanistic diversity in a metalloenzyme superfamily. Biochemistry 2000, 39, 13625–13632, doi:10.1021/bi001814v.
[67]
Leon, J.; Garcia-Lobo, J.M.; Navas, J.; Ortiz, J.M. Fosfomycin-resistance plasmids determine an intracellular modification of fosfomycin. J. Gen. Microbiol. 1985, 131, 1649–1655.
[68]
Llaneza, J.; Villar, C.J.; Salas, J.A.; Suarez, J.E.; Mendoza, M.C.; Hardisson, C. Plasmid-mediated fosfomycin resistance is due to enzymatic modification of the antibiotic. Antimicrob. Agents Chemother. 1985, 28, 163–164, doi:10.1128/AAC.28.1.163.
Garcia-Lobo, J.M.; Ortiz, J.M. Tn292l, a transposon encoding fosfomycin resistance. J. Bacteriol. 1982, 151, 477–479.
[71]
Seoane, A.; Sangari, F.J.; Lobo, J.M. Complete nucleotide sequence of the fosfomycin resistance transposon Tn2921. Int. J. Antimicrob. Agents 2010, 35, 413–414, doi:10.1016/j.ijantimicag.2009.12.006.
[72]
Rife, C.L.; Pharris, R.E.; Newcomer, M.E.; Armstrong, R.N. Crystal structure of a genomically encoded fosfomycin resistance protein (FosA) at 1.19 A resolution by MAD phasing off the L-III edge of Tl(+). J. Am. Chem. Soc. 2002, 124, 11001–11003, doi:10.1021/ja026879v.
[73]
Arca, P.; Hardisson, C.; Suarez, J.E. Purification of a glutathione S-transferase that mediates fosfomycin resistance in bacteria. Antimicrob. Agents Chemother. 1990, 34, 844–848, doi:10.1128/AAC.34.5.844.
[74]
Arca, P.; Rico, M.; Brana, A.F.; Villar, C.J.; Hardisson, C.; Suarez, J.E. Formation of an adduct between fosfomycin and glutathione: A new mechanism of antibiotic resistance in bacteria. Antimicrob. Agents Chemother. 1988, 32, 1552–1556, doi:10.1128/AAC.32.10.1552.
[75]
Bernat, B.A.; Laughlin, L.T.; Armstrong, R.N. Fosfomycin resistance protein (FosA) is a manganese metalloglutathione transferase related to glyoxalase I and the extradiol dioxygenases. Biochemistry 1997, 36, 3050–3055, doi:10.1021/bi963172a.
[76]
Bernat, B.A.; Armstrong, R.N. Elementary steps in the acquisition of Mn2+ by the fosfomycin resistance protein (FosA). Biochemistry 2001, 40, 12712–12718, doi:10.1021/bi0114832.
[77]
Bernat, B.A.; Laughlin, L.T.; Armstrong, R.N. Elucidation of a monovalent cation dependence and characterization of the divalent cation binding site of the fosfomycin resistance protein (FosA). Biochemistry 1999, 38, 7462–7469, doi:10.1021/bi990391y.
[78]
Beharry, Z.; Palzkill, T. Functional analysis of active site residues of the fosfomycin resistance enzyme FosA from Pseudomonas aeruginosa. J. Biol. Chem. 2005, 280, 17786–17791, doi:10.1074/jbc.M501052200.
[79]
Etienne, J.; Gerbaud, G.; Fleurette, J.; Courvalin, P. Characterization of staphylococcal plasmids hybridizing with the fosfomycin resistance gene fosB. FEMS Microbiol. Lett. 1991, 68, 119–122.
[80]
Zilhao, R.; Courvalin, P. Nucleotide sequence of the fosB gene conferring fosfomycin resistance in Staphylococcus epidermidis. FEMS Microbiol. Lett. 1990, 56, 267–272.
[81]
Cao, M.; Bernat, B.A.; Wang, Z.; Armstrong, R.N.; Helmann, J.D. FosB, a cysteine-dependent fosfomycin resistance protein under the control of sigma(W), an extracytoplasmic-function sigma factor in Bacillus subtilis. J. Bacteriol. 2001, 183, 2380–2383, doi:10.1128/JB.183.7.2380-2383.2001.
[82]
Butcher, B.G.; Helmann, J.D. Identification of Bacillus subtilis sigma-dependent genes that provide intrinsic resistance to antimicrobial compounds produced by Bacilli. Mol. Microbiol. 2006, 60, 765–782, doi:10.1111/j.1365-2958.2006.05131.x.
[83]
Gaballa, A.; Newton, G.L.; Antelmann, H.; Parsonage, D.; Upton, H.; Rawat, M.; Claiborne, A.; Fahey, R.C.; Helmann, J.D. Biosynthesis and functions of bacillithiol, a major low-molecular-weight thiol in Bacilli. Proc. Natl. Acad. Sci. USA 2010, 107, 6482–6486, doi:10.1073/pnas.1000928107.
[84]
Parsonage, D.; Newton, G.L.; Holder, R.C.; Wallace, B.D.; Paige, C.; Hamilton, C.J.; Dos Santos, P.C.; Redinbo, M.R.; Reid, S.D.; Claiborne, A. Characterization of the N-acetyl-alpha-d-glucosaminyl l-malate synthase and deacetylase functions for bacillithiol biosynthesis in Bacillus anthracis. Biochemistry 2010, 49, 8398–8414, doi:10.1021/bi100698n.
[85]
Roberts, A.A.; Sharma, S.V.; Strankman, A.W.; Duran, S.R.; Rawat, M.; Hamilton, C.J. Mechanistic studies of FosB: A divalent metal-dependent bacillithiol-S-transferase that mediates fosfomycin resistance in Staphylococcus aureus. Biochem. J. 2013, 451, 69–79, doi:10.1042/BJ20121541.
[86]
Fillgrove, K.L.; Pakhomova, S.; Newcomer, M.E.; Armstrong, R.N. Mechanistic diversity of fosfomycin resistance in pathogenic microorganisms. J. Am. Chem. Soc. 2003, 125, 15730–15731, doi:10.1021/ja039307z.
[87]
Fillgrove, K.L.; Pakhomova, S.; Schaab, M.R.; Newcomer, M.E.; Armstrong, R.N. Structure and mechanism of the genomically encoded fosfomycin resistance protein, FosX, from Listeria monocytogene. Biochemistry 2007, 46, 8110–8120, doi:10.1021/bi700625p.
[88]
Kobayashi, S.; Kuzuyama, T.; Seto, H. Characterization of the fomA and fomB gene products from Streptomyces wedmorensis, which confer fosfomycin resistance on Escherichia coli. Antimicrob. Agents Chemother. 2000, 44, 647–650, doi:10.1128/AAC.44.3.647-650.2000.
[89]
Kuzuyama, T.; Kobayashi, S.; O'Hara, K.; Hidaka, T.; Seto, H. Fosfomycin monophosphate and fosfomycin diphosphate, two inactivated fosfomycin derivates formed by gene products of fomA and fomB from a fosfomycin producing organism Streptomyces wedmorensis. J. Antibiot. (Tokyo) 1996, 49, 502–504, doi:10.7164/antibiotics.49.502.
[90]
Pakhomova, S.; Bartlett, S.G.; Augustus, A.; Kuzuyama, T.; Newcomer, M.E. Crystal structure of fosfomycin resistance kinase FomA from Streptomyces wedmorensis. J. Biol. Chem. 2008, 283, 28518–28526.
[91]
Garcia, P.; Arca, P.; Evaristo Suarez, J. Product of fosC, a gene from Pseudomonas syringae, mediates fosfomycin resistance by using ATP as cosubstrate. Antimicrob. Agents Chemother. 1995, 39, 1569–1573, doi:10.1128/AAC.39.7.1569.
[92]
Kim, S.Y.; Ju, K.S.; Metcalf, W.W.; Evans, B.S.; Kuzuyama, T.; van der Donk, W.A. Different biosynthetic pathways to fosfomycin in Pseudomonas syringae and Streptomyces species. Antimicrob. Agents Chemother. 2012, 56, 4175–4183, doi:10.1128/AAC.06478-11.
[93]
Arca, P.; Reguera, G.; Hardisson, C. Plasmid-encoded fosfomycin resistance in bacteria isolated from the urinary tract in a multicentre survey. J. Antimicrob. Chemother. 1997, 40, 393–399, doi:10.1093/jac/40.3.393.
[94]
O’Hara, K. Two different types of fosfomycin resistance in clinical isolates of Klebsiella pneumoniae. FEMS Microbiol. Lett. 1993, 114, 9–16, doi:10.1111/j.1574-6968.1993.tb06543.x.
[95]
Shimizu, M.; Shigeobu, F.; Miyakozawa, I.; Nakamura, A.; Suzuki, M.; Mizukoshi, S.; O’Hara, K.; Sawai, T. Novel fosfomycin resistance of Pseudomonas aeruginosa clinical isolates recovered in Japan in 1996. Antimicrob. Agents Chemother. 2000, 44, 2007–2008, doi:10.1128/AAC.44.7.2007-2008.2000.
[96]
Wachino, J.; Yamane, K.; Suzuki, S.; Kimura, K.; Arakawa, Y. Prevalence of fosfomycin resistance among CTX-M-producing Escherichia coli clinical isolates in Japan and identification of novel plasmid-mediated fosfomycin-modifying enzymes. Antimicrob. Agents Chemother. 2010, 54, 3061–3064, doi:10.1128/AAC.01834-09.
Ho, P.L.; Chan, J.; Lo, W.U.; Law, P.Y.; Li, Z.; Lai, E.L.; Chow, K.H. Dissemination of plasmid-mediated fosfomycin resistance fosA3 among multidrug-resistant Escherichia coli from livestock and other animals. J. Appl. Microbiol. 2013, 114, 695–702, doi:10.1111/jam.12099.
[99]
Hou, J.; Huang, X.; Deng, Y.; He, L.; Yang, T.; Zeng, Z.; Chen, Z.; Liu, J.H. Dissemination of the fosfomycin resistance gene fosA3 with CTX-M beta-lactamase genes and rmtB carried on IncFII plasmids among Escherichia coli isolates from pets in China. Antimicrob. Agents Chemother. 2012, 56, 2135–2138, doi:10.1128/AAC.05104-11.
[100]
He, L.; Partridge, S.R.; Yang, X.; Hou, J.; Deng, Y.; Yao, Q.; Zeng, Z.; Chen, Z.; Liu, J.H. Complete nucleotide sequence of pHN7A8, an F33:A-:B-type epidemic plasmid carrying blaCTX-M-65, fosA3 and rmtB from China. J. Antimicrob. Chemother. 2013, 68, 46–50, doi:10.1093/jac/dks369.
[101]
Shen, P.; Jiang, Y.; Zhou, Z.; Zhang, J.; Yu, Y.; Li, L. Complete nucleotide sequence of pKP96, a 67 850 bp multiresistance plasmid encoding qnrA1, aac(6')-Ib-cr and blaCTX-M-24 from Klebsiella pneumonia. J. Antimicrob. Chemother. 2008, 62, 1252–1256.
[102]
Lee, S.Y.; Park, Y.J.; Yu, J.K.; Jung, S.; Kim, Y.; Jeong, S.H.; Arakawa, Y. Prevalence of acquired fosfomycin resistance among extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae clinical isolates in Korea and IS26-composite transposon surrounding fosA3. J. Antimicrob. Chemother. 2012, 60, 329–336.
[103]
De Groote, V.N.; Fauvart, M.; Kint, C.I.; Verstraeten, N.; Jans, A.; Cornelis, P.; Michiels, J. Pseudomonas aeruginosa fosfomycin resistance mechanisms affect non-inherited fluoroquinolone tolerance. J. Med. Microbiol. 2011, 60, 329–336.
[104]
Nilsson, A.I.; Berg, O.G.; Aspevall, O.; Kahlmeter, G.; Andersson, D.I. Biological costs and mechanisms of fosfomycin resistance in Escherichia coli. Antimicrob. Agents Chemother. 2003, 47, 2850–2858.
[105]
Oteo, J.; Orden, B.; Bautista, V.; Cuevas, O.; Arroyo, M.; Martinez-Ruiz, R.; Perez-Vazquez, M.; Alcaraz, M.; Garcia-Cobos, S.; Campos, J. CTX-M-15-producing urinary Escherichia coli O25b-ST131-phylogroup B2 has acquired resistance to fosfomycin. J. Antimicrob. Chemother. 2009, 64, 712–717.
[106]
Rodriguez-Rojas, A.; Macia, M.D.; Couce, A.; Gomez, C.; Castaneda-Garcia, A.; Oliver, A.; Blazquez, J. Assesing the emergence of resistance: The absence of biological cost in vivo may compromise fosfomycin treatments for Pseudomonas aeruginosa infections. PLoS One 2010, 5, e10193.
