Plasmid-determined resistance to fosfomycin in Serratia marcescens

Mendoza, Carmen de; García, Juan Manuel Mijares; Llaneza, J.; Méndez, Francisco Javier; Hardisson, Carlos; Ortiz, José M.

doi:10.1128/aac.18.2.215

Cited by 73 publications

(52 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The bands of pUO430 and pUO900 hybridizing strongly with radioactive pUO200 corresponded to segments of DNA presumably carrying determinants of resistance common to all the plasmids as has been in part determined by their positive hybridization with pBR322 (see above). DISCUSSION The existence of plasmid-borne resistance to fosfomycin was initially reported because it was capable of being transferred by conjugation to susceptible strains (21). The resistance is not exerted through a permeability barrier to the drug, as is chromosomally mediated resistance (29) Cloning of the determinant of resistance to fosfomycin gives a practical advantage in epidemiological studies because it can be used as a genetic probe for the evaluation of the dispersion of the gene among plasmids and bacterial species not only in our environment, but also in other places where the use of fosfomycin is becoming common (4).…”

Section: Methodsmentioning

confidence: 99%

“…Plasmids carrying fosfomycin resistance have been found in Serratia marcescens and more recently in Klebsiella pneumoniae clinical strains. They have a high molecular weight, are conjugative, and carry resistances to other antibiotics (9,21). A transposon, Tn2921, carrying the For determinant has been identified in one of these plasmids, indicating a further means of dispersion of the resistance (7).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Cloning and molecular epidemiology of plasmid-determined fosfomycin resistance

Villar¹,

Hardisson²,

Súarez³

1986

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

The plasmid determinant of resistance to fosfomycin (For) was cloned into pBR322 and located in a 0.7-kilobase segment of DNA by transposon mutagenesis and in vitro deletion analysis. It encodes an 18-kilodalton protein located in the cytoplasm of resistant cells. Its synthesis is constitutive. The For genetic determinant is common to all plasmids isolated since 1975 in an hospital environment as determined by DNA-DNA hybridization. However, plasmids which carry For can be divided into two groups on the basis of size, pattern of antibiotic resistances, incompatibility specificity, and restriction and hybridization properties.

show abstract

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Cloning and molecular epidemiology of plasmid-determined fosfomycin resistance

Villar¹,

Hardisson²,

Súarez³

1986

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

show abstract

“…Furthermore, fosfomycin treatment leads to high urinary levels of drug (Ͼ1 mg/ml for 12 h after oral dosing [326]), which would likely kill off preexisting mutants (of the target or uptake type) resistant to lower concentrations; additionally, the total organismal load in uncomplicated UTI is probably Ͻ10 8 (based on calculations for E. coli in reference 272). In the clinic, fosfomycin resistance generally is due to covalent formation of a fosfomycin-glutathione adduct by FosA, FosB, and FosX enzymes which have spread by HGT (52,113,252).…”

Section: Fitness Of Resistant Mutants and Compensatory Mutationsmentioning

confidence: 99%

Challenges of Antibacterial Discovery

Silver¹

2011

Clin Microbiol Rev

1,136

961

View full text Add to dashboard Cite

SUMMARY The discovery of novel small-molecule antibacterial drugs has been stalled for many years. The purpose of this review is to underscore and illustrate those scientific problems unique to the discovery and optimization of novel antibacterial agents that have adversely affected the output of the effort. The major challenges fall into two areas: (i) proper target selection, particularly the necessity of pursuing molecular targets that are not prone to rapid resistance development, and (ii) improvement of chemical libraries to overcome limitations of diversity, especially that which is necessary to overcome barriers to bacterial entry and proclivity to be effluxed, especially in Gram-negative organisms. Failure to address these problems has led to a great deal of misdirected effort.

show abstract

“…Fos resistance is acquired mainly by reducing the cell's drug uptake (4,10,11,22), although active efflux, target alterations, and plasmid-encoded resistance have also been described in Escherichia coli and other species (18,21,23,24). Resistant mutations usually entail a moderate to high fitness cost (1,15,19), as well as reduced virulence (8,13,15), which has been invoked to explain the low prevalence of resistant strains (19).…”

mentioning

confidence: 99%

Genomewide Overexpression Screen for Fosfomycin Resistance in Escherichia coli: MurA Confers Clinical Resistance at Low Fitness Cost

Couce

Briales

Rodríguez‐Rojas

et al. 2012

Antimicrob Agents Chemother

View full text Add to dashboard Cite

To determine whether the overexpression of chromosomal genes can confer fosfomycin resistance, genomewide screening of a complete set of 5,272 plasmid-expressed open reading frames of Escherichia coli (ASKA collection) was performed. Major results are that (i) no clinical level of resistance is achieved by overexpressing chromosomal genes, except murA; (ii) this level is reached at a low fitness cost; and (iii) this cost is much lower than that imposed by other mutations conferring fosfomycin resistance.T he emergence of antibiotic resistance mutants in a bacterial population is shaped by several factors, and both the mutation rate and the fitness cost of resistance are particularly relevant (2). If resistance came at a high fitness cost, the growth rate would not be enough to offset the clearance imposed by the host or to prevent the bacteria from being outcompeted by fitter susceptible bacteria once the antibiotic is removed (2).Fosfomycin (Fos) is a broad-spectrum bactericidal antibiotic active against both Gram-positive and Gram-negative bacteria (7). Conveniently, Fos treatments have shown a relatively low likelihood that resistant mutants will persist in vivo, probably due to the high biological cost of resistance mutations, leading to good therapeutic effectiveness (19).Fos resistance is acquired mainly by reducing the cell's drug uptake (4,10,11,22), although active efflux, target alterations, and plasmid-encoded resistance have also been described in Escherichia coli and other species (18,21,23,24). Resistant mutations usually entail a moderate to high fitness cost (1,15,19), as well as reduced virulence (8,13,15), which has been invoked to explain the low prevalence of resistant strains (19). Despite this, a significant increase in resistance has been recently described after antibiotic pressure in the community (20), suggesting that there may be other, unidentified, ways to attain less costly high-level Fos resistance.The genome of E. coli harbors a substantial reservoir of resistance genes whose overexpression can decrease susceptibility (22). The complete E. coli open reading frame (ORF) ASKA library has already been screened for resistance to 237 toxins and antibiotics. However, Fos was not included among the drugs used to screen for resistance. Given the renewed interest in Fos treatment, we explored the capacity of the overexpression of chromosomal E. coli genes to confer clinical levels of Fos resistance by screening the complete ASKA library (12).Genomewide overexpression screening for Fos resistance. The complete ASKA library was replicated in duplicate in 96-well plates containing Luria-Bertani (LB) broth plus chloramphenicol (50 g/ml) with and without isopropyl-␤-D-thiogalactopyranoside (IPTG) to a final concentration of 100 M and incubated overnight at 37°C. The transcription of the cloned genes of the ASKA collection is under the control of the Ptac promoter, which is induced by the addition of IPTG (12). A 5-l sample from each well was spotted onto an LB agar plate containing either 32 g/...

show abstract

Plasmid-determined resistance to fosfomycin in Serratia marcescens

Cited by 73 publications

References 17 publications

Cloning and molecular epidemiology of plasmid-determined fosfomycin resistance

Cloning and molecular epidemiology of plasmid-determined fosfomycin resistance

Challenges of Antibacterial Discovery

Genomewide Overexpression Screen for Fosfomycin Resistance in Escherichia coli: MurA Confers Clinical Resistance at Low Fitness Cost

Contact Info

Product

Resources

About