Abstract
The mechanism of low-level glycopeptide resistance among staphylococci is not known. A cytoplasmic protein, provisionally called Ddh (W. M. Milewski, S. Boyle-Vavra, B. Moreira, C. C. Ebert, and R. S. Daum, Antimicrob. Agents Chemother. 40:166-172, 1996), and the RNA transcript that contains the ddh gene, which encodes Ddh, are present in increased amounts in a vancomycin-resistant isolate, 523k, compared with the susceptible parent isolate, 523. Sequence analysis had previously revealed that Ddh is related to NAD+-dependent D-lactate dehydrogenase (D-nLDH) and VanH. This latter protein is essential for high-level glycopeptide resistance in Enterococcus faecium and Enterococcus faecalis by synthesizing the D-lactate needed for biosynthesis of D-lactate-terminating peptidoglycan precursors with low affinity for vancomycin. We now provide the direct evidence that the ddh gene product is Staphylococcus aureus D-nLDH and hereafter refer to the protein as D-nLDH. However, overproduction of this protein in isolate 523k did not result in production of D-lactate-containing peptidoglycan precursors, and susceptibility testing of ddh mutants of 523k demonstrated that S. aureus D-nLDH is not necessary for glycopeptide resistance in this isolate. We conclude that the mechanism of glycopeptide resistance in this isolate is distinct from that in enterococci.
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Selected References
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- Arthur M., Molinas C., Courvalin P. The VanS-VanR two-component regulatory system controls synthesis of depsipeptide peptidoglycan precursors in Enterococcus faecium BM4147. J Bacteriol. 1992 Apr;174(8):2582–2591. doi: 10.1128/jb.174.8.2582-2591.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Arthur M., Molinas C., Dutka-Malen S., Courvalin P. Structural relationship between the vancomycin resistance protein VanH and 2-hydroxycarboxylic acid dehydrogenases. Gene. 1991 Jul 15;103(1):133–134. doi: 10.1016/0378-1119(91)90405-z. [DOI] [PubMed] [Google Scholar]
- Arthur M., Reynolds P., Courvalin P. Glycopeptide resistance in enterococci. Trends Microbiol. 1996 Oct;4(10):401–407. doi: 10.1016/0966-842X(96)10063-9. [DOI] [PubMed] [Google Scholar]
- Augustin J., Götz F. Transformation of Staphylococcus epidermidis and other staphylococcal species with plasmid DNA by electroporation. FEMS Microbiol Lett. 1990 Jan 1;54(1-3):203–207. doi: 10.1016/0378-1097(90)90283-v. [DOI] [PubMed] [Google Scholar]
- Barna J. C., Williams D. H. The structure and mode of action of glycopeptide antibiotics of the vancomycin group. Annu Rev Microbiol. 1984;38:339–357. doi: 10.1146/annurev.mi.38.100184.002011. [DOI] [PubMed] [Google Scholar]
- Biavasco F., Giovanetti E., Montanari M. P., Lupidi R., Varaldo P. E. Development of in-vitro resistance to glycopeptide antibiotics: assessment in staphylococci of different species. J Antimicrob Chemother. 1991 Jan;27(1):71–79. doi: 10.1093/jac/27.1.71. [DOI] [PubMed] [Google Scholar]
- Billot-Klein D., Gutmann L., Bryant D., Bell D., Van Heijenoort J., Grewal J., Shlaes D. M. Peptidoglycan synthesis and structure in Staphylococcus haemolyticus expressing increasing levels of resistance to glycopeptide antibiotics. J Bacteriol. 1996 Aug;178(15):4696–4703. doi: 10.1128/jb.178.15.4696-4703.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Billot-Klein D., Gutmann L., Sablé S., Guittet E., van Heijenoort J. Modification of peptidoglycan precursors is a common feature of the low-level vancomycin-resistant VANB-type Enterococcus D366 and of the naturally glycopeptide-resistant species Lactobacillus casei, Pediococcus pentosaceus, Leuconostoc mesenteroides, and Enterococcus gallinarum. J Bacteriol. 1994 Apr;176(8):2398–2405. doi: 10.1128/jb.176.8.2398-2405.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bugg T. D., Dutka-Malen S., Arthur M., Courvalin P., Walsh C. T. Identification of vancomycin resistance protein VanA as a D-alanine:D-alanine ligase of altered substrate specificity. Biochemistry. 1991 Feb 26;30(8):2017–2021. doi: 10.1021/bi00222a002. [DOI] [PubMed] [Google Scholar]
- Bugg T. D., Wright G. D., Dutka-Malen S., Arthur M., Courvalin P., Walsh C. T. Molecular basis for vancomycin resistance in Enterococcus faecium BM4147: biosynthesis of a depsipeptide peptidoglycan precursor by vancomycin resistance proteins VanH and VanA. Biochemistry. 1991 Oct 29;30(43):10408–10415. doi: 10.1021/bi00107a007. [DOI] [PubMed] [Google Scholar]
- Daum R. S., Gupta S., Sabbagh R., Milewski W. M. Characterization of Staphylococcus aureus isolates with decreased susceptibility to vancomycin and teicoplanin: isolation and purification of a constitutively produced protein associated with decreased susceptibility. J Infect Dis. 1992 Nov;166(5):1066–1072. doi: 10.1093/infdis/166.5.1066. [DOI] [PubMed] [Google Scholar]
- Evers S., Sahm D. F., Courvalin P. The vanB gene of vancomycin-resistant Enterococcus faecalis V583 is structurally related to genes encoding D-Ala:D-Ala ligases and glycopeptide-resistance proteins VanA and VanC. Gene. 1993 Feb 14;124(1):143–144. doi: 10.1016/0378-1119(93)90779-3. [DOI] [PubMed] [Google Scholar]
- Feinberg A. P., Vogelstein B. "A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity". Addendum. Anal Biochem. 1984 Feb;137(1):266–267. doi: 10.1016/0003-2697(84)90381-6. [DOI] [PubMed] [Google Scholar]
- Garrard W., Lascelles J. Regulation of Staphylococcus aureus lactate dehydrogenase. J Bacteriol. 1968 Jan;95(1):152–156. doi: 10.1128/jb.95.1.152-156.1968. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Garvie E. I. Bacterial lactate dehydrogenases. Microbiol Rev. 1980 Mar;44(1):106–139. doi: 10.1128/mr.44.1.106-139.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Greenwood D., Bidgood K., Turner M. A comparison of the responses of staphylococci and streptococci to teicoplanin and vancomycin. J Antimicrob Chemother. 1987 Aug;20(2):155–164. doi: 10.1093/jac/20.2.155. [DOI] [PubMed] [Google Scholar]
- Handwerger S. Alterations in peptidoglycan precursors and vancomycin susceptibility in Tn917 insertion mutants of Enterococcus faecalis 221. Antimicrob Agents Chemother. 1994 Mar;38(3):473–475. doi: 10.1128/aac.38.3.473. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Handwerger S., Pucci M. J., Volk K. J., Liu J., Lee M. S. Vancomycin-resistant Leuconostoc mesenteroides and Lactobacillus casei synthesize cytoplasmic peptidoglycan precursors that terminate in lactate. J Bacteriol. 1994 Jan;176(1):260–264. doi: 10.1128/jb.176.1.260-264.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Herwaldt L., Boyken L., Pfaller M. In vitro selection of resistance to vancomycin in bloodstream isolates of Staphylococcus haemolyticus and Staphylococcus epidermidis. Eur J Clin Microbiol Infect Dis. 1991 Dec;10(12):1007–1012. doi: 10.1007/BF01984921. [DOI] [PubMed] [Google Scholar]
- Hiramatsu K., Hanaki H., Ino T., Yabuta K., Oguri T., Tenover F. C. Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility. J Antimicrob Chemother. 1997 Jul;40(1):135–136. doi: 10.1093/jac/40.1.135. [DOI] [PubMed] [Google Scholar]
- Kaatz G. W., Seo S. M., Dorman N. J., Lerner S. A. Emergence of teicoplanin resistance during therapy of Staphylococcus aureus endocarditis. J Infect Dis. 1990 Jul;162(1):103–108. doi: 10.1093/infdis/162.1.103. [DOI] [PubMed] [Google Scholar]
- Kreiswirth B. N., Löfdahl S., Betley M. J., O'Reilly M., Schlievert P. M., Bergdoll M. S., Novick R. P. The toxic shock syndrome exotoxin structural gene is not detectably transmitted by a prophage. Nature. 1983 Oct 20;305(5936):709–712. doi: 10.1038/305709a0. [DOI] [PubMed] [Google Scholar]
- Luchansky J. B., Benson A. K., Atherly A. G. Construction, transfer and properties of a novel temperature-sensitive integrable plasmid for genomic analysis of Staphylococcus aureus. Mol Microbiol. 1989 Jan;3(1):65–78. doi: 10.1111/j.1365-2958.1989.tb00105.x. [DOI] [PubMed] [Google Scholar]
- MCGUIRE J. M., WOLFE R. N., ZIEGLER D. W. Vancomycin, a new antibiotic. II. In vitro antibacterial studies. Antibiot Annu. 1955;3:612–618. [PubMed] [Google Scholar]
- Mainardi J. L., Shlaes D. M., Goering R. V., Shlaes J. H., Acar J. F., Goldstein F. W. Decreased teicoplanin susceptibility of methicillin-resistant strains of Staphylococcus aureus. J Infect Dis. 1995 Jun;171(6):1646–1650. doi: 10.1093/infdis/171.6.1646. [DOI] [PubMed] [Google Scholar]
- Mat-Jan F., Alam K. Y., Clark D. P. Mutants of Escherichia coli deficient in the fermentative lactate dehydrogenase. J Bacteriol. 1989 Jan;171(1):342–348. doi: 10.1128/jb.171.1.342-348.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Milewski W. M., Boyle-Vavra S., Moreira B., Ebert C. C., Daum R. S. Overproduction of a 37-kilodalton cytoplasmic protein homologous to NAD+-linked D-lactate dehydrogenase associated with vancomycin resistance in Staphylococcus aureus. Antimicrob Agents Chemother. 1996 Jan;40(1):166–172. doi: 10.1128/aac.40.1.166. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moreira B., Boyle-Vavra S., deJonge B. L., Daum R. S. Increased production of penicillin-binding protein 2, increased detection of other penicillin-binding proteins, and decreased coagulase activity associated with glycopeptide resistance in Staphylococcus aureus. Antimicrob Agents Chemother. 1997 Aug;41(8):1788–1793. doi: 10.1128/aac.41.8.1788. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Muller E., Hübner J., Gutierrez N., Takeda S., Goldmann D. A., Pier G. B. Isolation and characterization of transposon mutants of Staphylococcus epidermidis deficient in capsular polysaccharide/adhesin and slime. Infect Immun. 1993 Feb;61(2):551–558. doi: 10.1128/iai.61.2.551-558.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Novick R. P. Genetic systems in staphylococci. Methods Enzymol. 1991;204:587–636. doi: 10.1016/0076-6879(91)04029-n. [DOI] [PubMed] [Google Scholar]
- O'Hare M. D., Reynolds P. E. Novel membrane proteins present in teicoplanin-resistant, vancomycin-sensitive, coagulase-negative Staphylococcus spp. J Antimicrob Chemother. 1992 Dec;30(6):753–768. doi: 10.1093/jac/30.6.753. [DOI] [PubMed] [Google Scholar]
- Park I. S., Lin C. H., Walsh C. T. Gain of D-alanyl-D-lactate or D-lactyl-D-alanine synthetase activities in three active-site mutants of the Escherichia coli D-alanyl-D-alanine ligase B. Biochemistry. 1996 Aug 13;35(32):10464–10471. doi: 10.1021/bi9603128. [DOI] [PubMed] [Google Scholar]
- Patti J. M., Bremell T., Krajewska-Pietrasik D., Abdelnour A., Tarkowski A., Rydén C., Hök M. The Staphylococcus aureus collagen adhesin is a virulence determinant in experimental septic arthritis. Infect Immun. 1994 Jan;62(1):152–161. doi: 10.1128/iai.62.1.152-161.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reynolds P. E., Depardieu F., Dutka-Malen S., Arthur M., Courvalin P. Glycopeptide resistance mediated by enterococcal transposon Tn1546 requires production of VanX for hydrolysis of D-alanyl-D-alanine. Mol Microbiol. 1994 Sep;13(6):1065–1070. doi: 10.1111/j.1365-2958.1994.tb00497.x. [DOI] [PubMed] [Google Scholar]
- Shlaes D. M., Shlaes J. H., Vincent S., Etter L., Fey P. D., Goering R. V. Teicoplanin-resistant Staphylococcus aureus expresses a novel membrane protein and increases expression of penicillin-binding protein 2 complex. Antimicrob Agents Chemother. 1993 Nov;37(11):2432–2437. doi: 10.1128/aac.37.11.2432. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sieradzki K., Tomasz A. A highly vancomycin-resistant laboratory mutant of Staphylococcus aureus. FEMS Microbiol Lett. 1996 Sep 1;142(2-3):161–166. doi: 10.1111/j.1574-6968.1996.tb08424.x. [DOI] [PubMed] [Google Scholar]
- Tarmy E. M., Kaplan N. O. Chemical characterization of D-lactate dehydrogenase from Escherichia coli B. J Biol Chem. 1968 May 25;243(10):2579–2586. [PubMed] [Google Scholar]
- Tarmy E. M., Kaplan N. O. Kinetics of Escherichia coli B D-lactate dehydrogenase and evidence for pyruvate-controlled change in conformation. J Biol Chem. 1968 May 25;243(10):2587–2596. [PubMed] [Google Scholar]