Resistance glycopeptides

Arthur M., Reynolds P. Courvalin P. (1996) Glycopeptide resistance in enterococci. Trends Microbiol, 4,401-407. 

Acquired resistance to the glycopeptides is transposon-mediated and has so far been largely confined to the enterococci. This has been a problem clinically because many of these strains have been resistant to all other antibiotics and were thus effectively untreatable. Fortunately, the enterococci are not particularly pathogenic and infections have been confined largely to seriously ill, long-term hospital patients. Two types of acquired glycopeptide resistance have been described (Woodford et al. 1995). The VanA phenotype is resistant to vancomycin and teicoplanin, whereas VanB is resistant... 

Fig. 9.4 Organization of glycopeptide-resistance genes in transposon Tnl546. IR, invested repeats HPK, histidine protein kinase TcR, low level teicoplanin resistance.

The origins of the glycopeptide-resistance genes are unknown and share little homology with genes found in intrinsically glycopeptide-resistant organisms. 

Woodford N., Johnson AP., Morrison D. Speller D.C. (1995) Current perspectives on glycopeptide resistance. Clin Microbiol Rev, 8, 585-615. 

Arthur, M. Molinas, C. Depardieu, E Courvalin, P Characterization of Tnl546, a Tn3-related transposon conferring glycopeptide resistance by synthesis of depsipeptide peptidoglycan precursors in Enterococcus faecium BM4147. J. Bacteriol., 175, 117-127 (1993)... 

Zirakzadeh A, Patel R. Epidemiology and mechanisms of glycopeptide resistance in enterococci. Curr Opin Infect Dis. 2005 18 507-512. 

M Arthur, P Courvalin. Genetics and mechanism of glycopeptide resistance in enterococci. Antimicrob Agents Chemother 37 1563-1571, 1993. 

PE Reynolds, F Depardieu, S Dutka-Malen, M Arthur, P Courvalin. Glycopeptide resistance mediated by enterococcal transposon Tnl546 requires production of VanX for hydrolysis of D-alanyl-D-alanine. Mol Microbiol 13, 1065-1070, 1994. 

TI Nicas, ML Zekel, DK Braun. Beyond vancomycin new therapies to meet the challenge of glycopeptide resistance. Trends Microbiol 5 240-249, 1997. 

Over the past decade the emergence of resistant enterococci and S. aureus strains has been observed in clinics. Already, nowadays, the increase of glycopeptide-resistant... 

Thus far, the reasons for glycopeptide-resistance of S. aureus strains are not entirely clear. It is assumed that an increased biosynthesis of cell wall precursors combined with a thickened cell wall are the likely reasons.However, also the transferance of enterococcal resistance to S. aureus has been shown in the... 

Scheme 2-5. Molecular basis of enterococcal vanA/B- and vanC-glycopeptide resistance. Interaction of vancomycin with D-Ala-D-Lac. The lactate ester bond leads to a lowered ligand binding affinity by loss of one hydrogen bond and electronic repulsion (solid arrow).

The originally nonbiased modifications of glycopeptide molecules used in SAR studies together with the knowledge on the mode of action, stimulated researchers to develop more rational and sophisticated approaches and concepts to raise antibiotic activity of glycopeptide derivatives also against glycopeptide-resistant bacterial strains. A selection of these approaches is discussed in the subsequent sections. 

After 5 days administration of quinupristin + dalfopristin 7.5 mg/kg infused over 1 hour bd, the fecal microflora in 20 healthy volunteers increased significantly during treatment and returned within 12 weeks to baseUne concentrations after the end of treatment. There were anerobes and enterococci resistant to erythromycin or to quinupristin - - dalfopristin, but glycopeptide-resistant enterococci did not emerge (22). 

Verma A, Dhawan A, Philpott-Howard J, Rela M, Heaton N, Vergani GM, Wade J. Glycopeptide-resistant Enterococcus faecium infections in paediatric liver transplant recipients safety and clinical efficacy of quinupristin/ dalfopristin. J Antimicrob Chemother 2001 47(l) 105-8. 

In a study of antibiotic resistance in enterococci from raw meat, there was a high prevalence of glycopeptide-resistant strains (49). Resistance to vancomycin was significantly associated with resistance to teicoplanin, erythromycin, tetracycline, and chloramphenicol. 

Glycopeptide resistance in a cluster of three clinical isolates of vancomycin-resistant Enterococcus faecium was due to vanD, which was located on the chromosome and was not transferable to other enterococci These isolates were indistinguishable but differed from the strain in which vanD-mediated resistance has been reported previously (102). A type of acquired glycopeptide resistance, named vanE, has been characterized in E. faecalis BM 4405. It results in low-level resistance of vancomycin but susceptibility to teico-planin (103). Defects in penicillin-binding protein 4 result in a distorted peptidoglycan composition of the cell of vancomycin-resistant and teicoplanin-resistant laboratory mutants of S. aureus and are suggested to be part of the mechanism of glycopeptide resistance in these microbes (104). 

Fines M, Perichon B, Reynolds P, Sahm DF, Courvalin P. VanE, a new type of acquired glycopeptide resistance in Enterococcus faecalis BM4405. Antimicrob Agents Chemother 1999 43(9) 2161-4. 

Sieradzki K, Pinho MG, Tomasz A. Inactivated pbp4 in highly glycopeptide-resistant laboratory mutants of Staphylococcus aureus. J Biol Chem 1999 274(27) 18942-6. 

Descheemaeker P, Leven M, ChapeUe S, Lammens C, Hauchecome M, Wijdooghe M, Vandamme P, Goossens H (2000) Prevalence and molecular epidemiology of glycopeptide-resistant enterococd in Belgian renal dialysis units. J Infect Dis 181 235-241... 

Dutka-Malen S, Evers S, Courvalin P (1995) Detection of glycopeptide resistance genotypes and identification to the species level of clinically relevant enterococci by PCR. J Clin Microbiol 33 24-27... 

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