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Category: Bacterial Pathogenesis
Resistance to Glycopeptides in Gram-Positive Pathogens, Page 1 of 2
< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555816513/9781555813437_Chap63-1.gif /docserver/preview/fulltext/10.1128/9781555816513/9781555813437_Chap63-2.gifAbstract:
Glycopeptide antimicrobials are natural products that are produced by various soil-dwelling species of the order Actinomycetales such as Amycolatopsis orientalis and Amycolatopsis coloradensis. With the recent emergence of glycopeptide-resistant enterococci and staphylococci, there has been renewed interest by the pharmaceutical industry in the development of modified semisynthetic glycopeptides with enhanced activity against resistant gram-positive pathogens including glycopeptide-resistant organisms. Due to glycopeptides' unique mechanism of action and ability to interfere with multiple critical reactions in peptidoglycan synthesis, acquired resistance to glycopeptides was deemed unlikely. The mechanisms of acquired resistance to glycopeptides in enterococci have been well characterized and reflect changes in target analogous to those in intrinsically resistant organisms. The newer, semisynthetic glycopeptides oritavancin and telavancin have enhanced activity against some strains of enterococci with acquired glycopeptide resistance. The basis of both intrinsic and acquired glycopeptide resistance in enterococci involves alteration of the composition of the terminal dipeptide in muramyl pentapeptide cell wall precursors, resulting in a structure with decreased binding affinity for glycopeptides. Two additional enterococcal resistance genotypes, vanE and vanG, have also recently been described. Both are characterized by low-level vancomycin resistance mediated through the synthesis of precursors terminating in D-Ala-DSer analogous to the mechanism of VanC-type resistance. The chromosomally located five-gene vanE resistance cluster from Enterococcus faecalis BM4405 is organized very similarly to the vanC operon and includes genes encoding the VanE ligase, the VanXYE D,D-dipeptidase-D,D-carboxypeptidase, and the VanTE serine racemase, as well as the VanRESE two-component regulator.
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Increases in vancomycin usage (in kilograms) worldwide (primarily in the United States) from 1979 to 1983 and in the United States from 1984 to 1996 (◊—◊) that parallels the emergence of MRSA as a percentage of S. aureus isolates from large teaching hospitals in the United States from 1975 to 1989 (■ ■) and as a percentage of nosocomial S. aureus isolates from ICU (●—●) and non-ICU (▲—▲) settings from 1989 to 2003 ( 33 , 43 , 50 ). Rates of VRE in ICU (○—○) and non-ICU (∆—∆) settings begin to rise a decade after the dramatic increase in vancomycin usage ( 48 ). Also shown is the appearance of clinical VISA isolates in the United States in 1997 and VRSA in 2002, though these remain a very small percentage of total S. aureus strains.
Increases in vancomycin usage (in kilograms) worldwide (primarily in the United States) from 1979 to 1983 and in the United States from 1984 to 1996 (◊—◊) that parallels the emergence of MRSA as a percentage of S. aureus isolates from large teaching hospitals in the United States from 1975 to 1989 (■ ■) and as a percentage of nosocomial S. aureus isolates from ICU (●—●) and non-ICU (▲—▲) settings from 1989 to 2003 ( 33 , 43 , 50 ). Rates of VRE in ICU (○—○) and non-ICU (∆—∆) settings begin to rise a decade after the dramatic increase in vancomycin usage ( 48 ). Also shown is the appearance of clinical VISA isolates in the United States in 1997 and VRSA in 2002, though these remain a very small percentage of total S. aureus strains.
Structure of the glycopeptide; the peptidyl-D-Ala-D-Ala complex. Binding of the glycopeptide to the D-Ala-D-Ala residue on a peptidoglycan precursor involves five hydrogen bond interactions (indicated by the dashed lines). In D-Ala-D-Lac-terminating precursors, the NH of the amide group (*) is replaced by an oxygen in an ester linkage, eliminating the central hydrogen bond. In D-Ala-D-Ser-terminating precursors, the methyl side chain of the carboxy-terminal D-Ala (^) is replaced by a hydroxymethyl (CH2OH) side chain.
Structure of the glycopeptide; the peptidyl-D-Ala-D-Ala complex. Binding of the glycopeptide to the D-Ala-D-Ala residue on a peptidoglycan precursor involves five hydrogen bond interactions (indicated by the dashed lines). In D-Ala-D-Lac-terminating precursors, the NH of the amide group (*) is replaced by an oxygen in an ester linkage, eliminating the central hydrogen bond. In D-Ala-D-Ser-terminating precursors, the methyl side chain of the carboxy-terminal D-Ala (^) is replaced by a hydroxymethyl (CH2OH) side chain.
Transglycosylation and subsequent reactions in the cell wall synthesis pathway catalyzed by PBPs. Binding of glycopeptide to the terminal D-Ala-D-Ala stem inhibits both the transglycosylation reaction and the subsequent carboxypeptidase and transpeptidase steps. In the initial step of the carboxypeptidase or transpeptidase reactions, the terminal D-Ala is cleaved during the initial binding of the active serine site of the PBPs to form the acyl-enzyme complex. The same acylenzyme intermediate would be produced if the terminal D-Ala residue were replaced by either D-Lac or D-Ser. (Adapted from reference 9 ).
Transglycosylation and subsequent reactions in the cell wall synthesis pathway catalyzed by PBPs. Binding of glycopeptide to the terminal D-Ala-D-Ala stem inhibits both the transglycosylation reaction and the subsequent carboxypeptidase and transpeptidase steps. In the initial step of the carboxypeptidase or transpeptidase reactions, the terminal D-Ala is cleaved during the initial binding of the active serine site of the PBPs to form the acyl-enzyme complex. The same acylenzyme intermediate would be produced if the terminal D-Ala residue were replaced by either D-Lac or D-Ser. (Adapted from reference 9 ).
Structure of Tn1546 (10,851 bp) carrying the vanA vancomycin resistance gene cluster. The nine ORFs are delineated by 38-bp imperfect inverted repeats and include genes with resolvase and transposase activity (ORF1 and -2), as well as genes involved in regulation (vanR and vanS), synthesis of D-Ala-D-Lac (vanH and vanA), and hydrolysis of D-Ala-D-Ala precursors (vanX and vanY). The percent G+C content of each gene is also shown.
Structure of Tn1546 (10,851 bp) carrying the vanA vancomycin resistance gene cluster. The nine ORFs are delineated by 38-bp imperfect inverted repeats and include genes with resolvase and transposase activity (ORF1 and -2), as well as genes involved in regulation (vanR and vanS), synthesis of D-Ala-D-Lac (vanH and vanA), and hydrolysis of D-Ala-D-Ala precursors (vanX and vanY). The percent G+C content of each gene is also shown.
General scheme of peptidoglycan synthesis in GRE. The enterococcal Ddl ligases produce D-Ala-D-Ala residues that are incorporated into peptidoglycan precursors. D-Ala-D-Ala-terminating precursors interact with glycopeptides, preventing transglycosylation and leading to the accumulation of cytoplasmic precursors. The VanRS signal-transducing system responds directly or indirectly (via accumulation of cytoplasmic precursors) to the presence of glycopeptides leading to induction of transcription of the vanHAX operon in the cytoplasm. Induction of these genes results in production of D-Lac-containing precursors, as well as elimination of the pool of D-Ala-D-Ala precursors. (Adapted from reference 9 .)
General scheme of peptidoglycan synthesis in GRE. The enterococcal Ddl ligases produce D-Ala-D-Ala residues that are incorporated into peptidoglycan precursors. D-Ala-D-Ala-terminating precursors interact with glycopeptides, preventing transglycosylation and leading to the accumulation of cytoplasmic precursors. The VanRS signal-transducing system responds directly or indirectly (via accumulation of cytoplasmic precursors) to the presence of glycopeptides leading to induction of transcription of the vanHAX operon in the cytoplasm. Induction of these genes results in production of D-Lac-containing precursors, as well as elimination of the pool of D-Ala-D-Ala precursors. (Adapted from reference 9 .)
Comparison of the organization of the enterococcal D-Ala-D-Lac glycopeptide resistance operons vanA, vanB, and vanD and the enterococcal D-Ala-D-Ser glycopeptide resistance operons vanC, vanE, and vanG. The G+C content of the respective genes is also shown. The percent amino acid identities of the various genes to their homologs in the other enterocococcal resistance clusters are listed underneath each cluster ( Table 2 ).
Comparison of the organization of the enterococcal D-Ala-D-Lac glycopeptide resistance operons vanA, vanB, and vanD and the enterococcal D-Ala-D-Ser glycopeptide resistance operons vanC, vanE, and vanG. The G+C content of the respective genes is also shown. The percent amino acid identities of the various genes to their homologs in the other enterocococcal resistance clusters are listed underneath each cluster ( Table 2 ).
Genotypic and phenotypic characterization of GRE
a Expressed as MIC of vancomycin (Vanco) or teicoplanin (Teico) as micrograms per milliliter.
b Rare isolates described.
c MICs lower for E. faecalis strains.
Genotypic and phenotypic characterization of GRE
a Expressed as MIC of vancomycin (Vanco) or teicoplanin (Teico) as micrograms per milliliter.
b Rare isolates described.
c MICs lower for E. faecalis strains.
Van alphabet
a In enterococcal glycopeptide resistance operons.
Van alphabet
a In enterococcal glycopeptide resistance operons.
Characteristics and methods used for detection of Staphylococcus aureus clinical isolates with reduced susceptibility to glycopeptides
a Strains for which MICs of 8 to 16 μg/ml are defined as intermediately resistant by the NCCLS and the Comité de l' Antibiogramme de la Société Française de Microbiologie but are defined as resistant by the British Society for Antimicrobial Chemotherapy and the Swedish Reference Group for Antibiotics.
Characteristics and methods used for detection of Staphylococcus aureus clinical isolates with reduced susceptibility to glycopeptides
a Strains for which MICs of 8 to 16 μg/ml are defined as intermediately resistant by the NCCLS and the Comité de l' Antibiogramme de la Société Française de Microbiologie but are defined as resistant by the British Society for Antimicrobial Chemotherapy and the Swedish Reference Group for Antibiotics.
Mechanisms of resistance and clinical significance of VISA, VHRSA, and VRSA strains
a Described for some clinical or laboratory strains.
Mechanisms of resistance and clinical significance of VISA, VHRSA, and VRSA strains
a Described for some clinical or laboratory strains.