Fosfomycin resistance

Figure 1 The action of the antibiotic fosfomycin requires an active-site Cys residue in the target MurA. Substitution of Asp for Cys in some bacterial species results in intrinsic fosfomycin resistance.

De Smet KA, Kempsell KE, Gallagher A, Duncan K, Young DB. Alteration of a single amino acid residue reverses fosfomycin resistance of recombinant MurA from Mycobacterium tuberculosis. Microbiology 1999 145 3177-3184. 

Eillgrove KL, Pakhomova S, Newcomer ME, Arutstrong RN. Mechanistic diversity of fosfomycin resistance in pathogenic mi- 39. croorganisms. J. Am. Chem Soc. 2003 125 15730-15731. 

Suarez, J.E., and Mendoza. M.C., Plasmid-encoded fosfomycin resistance, Antimicrob. Agents Chemother., 35, 791, 1991. 

Zilhao, R., and Courvalin. P.. Nucleotide sequence of the fosB gene coiifeiring fosfomycin resistance in Staphylococcus epideniiidis, FEMS Microbial. Lett., 68, 267, 1990. 

Furthermore, if the antibiotic passes membranes through a specific port of entry, its mutational loss leads to resistance. The lack of the outer membrane protein OprD in P. aeruginosa causes resistance to the (3-lactam antibiotic imipenem. Fosfomycin passes the cytoplasmic membrane via an L-a-glycerol phosphate permease. This transport system is not essential for bacterial growth and therefore mutants with a reduced expression are frequently selected under therapy. 

Fosfomycin inhibits pyruvil transferase, which is an enzyme involved in peptidoglycan synthesis. Two mechanisms of acquired resistance have been described for fosfomycin (Davies 1994). 

Plasmid- ortransposon-mediated resistance occurs by inactivation ofthe antibiotic. Fosfomycin is combined with glutathione intracellularly to produce a compound lacking in antibacterial activity. The gene encoding the enzyme catalysing this reaction has been designated/or-r. 

A second mechanism of acquired resistance to fosfomycin involves chromosomal mutations in sugar phosphate uptake pathways which are responsible for transporting fosfomycin into the cell. The alterations decrease accumulation of the antibiotic to levels below those required for inhibition. 

Forward approach, to qualitative reliability analysis, 26 984 Forward-roll coaters, 7 12-13 method summarized, 7 5t shear rates, 7 32t Fosamine-ammonium, 13 320 Fosfomycin, bacterial resistance mechanisms, 3 32t... 

The absence of a sensitive microbial target is also a form of genetic intrinsic resistance. The oxirane antibiotic fosfomycin covalently modifies the target protein MurA on a sensitive and catalytically relevant Cys residue (Fig. 1) (10). MurA catalyzes the formation of Al-acetyhnuramic acid via enoylpyru-vyl transfer of phosphoenol pyruvate onto the acceptor sugar... 

A-acetylglucosamine, providing the necessary carboxylate anchor for attachment of the pentapeptide required for bacterial peptidoglycan (cell wall) formation. Bacteria that encode a MurA orthologue where the susceptible Cys is replaced by an Asp (e.g., Mycobacteria) are intrinsically genetically resistant to fosfomycin (Fig. 1) (11, 12). 

CT. Characterization of a CysllS to Asp substitution in the Escherichia coli cell wall biosynthetic enzyme UDP-GlcNAc enolpymvyl transferase (MurA) that confers resistance to in- 32. activation by the antibiotic fosfomycin. Biochemistry 1996 35 4923 928. 33. 

Fosfomycin has relatively low toxicity. Its penetration into tissues, including bones and joints, and into the cerebrospinal fluid is good. When given orally (2-3 g/day), it can produce gastrointestinal distress when injected intramuscularly, it can cause local pain. Fosfomycin is recommended in daily doses of 4-16 g intravenously for the treatment of severe infections resistant to other commonly used antibiotics. Fosfomycin diffuses moderately well into bone tissue (2). 

Area, P, Rico, M., Brana, A.E, Villar, C.J., Hardisson, C., and Suarez, J.E., Formation of an adduct between fosfomycin and glutathione. A new mechanism of antibiotic resistance in bacteria, Antimicrob. Agents Chemother, 32, 1552, 1988. 

Ampicillin, amoxicillin Doxycycline, fosfomycin, or nitrofurantoin E. faecium (generally more resistant to antibiotics than E. faecalis) Recommend consultation with infectious disease specialist. Linezolid, quinupristin/dalfopristin Staphylococcus aureus/Staphylococcus epidermidis Methicillin (oxacillin)-sensitive PRP"... 

As a signihcant percentage of urinary tract infections in many parts of the world are caused by sulfonamide-resistant microorganisms, snlfonamides are no longer a therapy of first choice. Trimethoprim-sulfamethoxazole, a quinolone, trimethoprim, fosfomycin, or ampicillin are the preferred agents. 

B. Fosfomycin Fosfomycin is an anti metabolite inhibitor of cytosolic enolpyruvate transferase. This action prevents the formation of A-acetylmuramic acid, an essential precursor molecule for peptidoglycan chain formation. Resistance to fosfomycin occurs via decreased intracellular accumulation of the drug. 

Fosfomycin is excreted by the kidney, with urinary levels exceeding the minimal inhibitory concentrations (MiCs) for many urinaiy tract pathogens. In a single dose, the drug is less effective than a 7-day course of treatment with fluoroquinolones. With multiple dosing, resistance emerges rapidly and diarrhea is common. Fosfomycin may be synergistic with beta-lactam and quinolone antibiotics in specific infections. 

Fosfomycin is one of a few natural products containing a carbon-phosphorus (C— P) bond isolated from Streptomyces fradiae, Streptomyces viridochromogenes, and Streptomyces wedmorensis [73]. It was also isolated from Pseudomonas syringae and Pseudomonas viridiflava [74, 75], Fosfomycin is a highly effective antibiotic of low toxicity clinically utilized for the treatment of lower urinary tract infections [76] as well as methicillin-resistant [77] and vancomycin-resistant [78] strains of S. aureus. Moreover, fosfomycin is effective for the treatment of cephalosporin- and penicillin-resistant Streptococcus pneumonia [79] and ciprofloxacin-resistant E. coli [80], The antimicrobial activity of fosfomycin has been ascribed to the inactivation of UDP-GlcAAc-3-O-enolpyruvyltransferase (MurA), an essential enzyme that catalyzes the first committed step in the biosynthesis of peptidoglycan, the main component of the cell wall, by covalent alkylation of an active site cysteine [81]. 

---