The d -Alanine Residues of Staphylococcus aureus Teichoic Acids Alter the Susceptibility to Vancomycin and the Activity of Autolytic Enzymes

Abstract

Recently, Staphylococcus aureus strains with intermediate resistance to vancomycin, the antibiotic of last resort, have been described. Multiple changes in peptidoglycan turnover and structure contribute to the resistance phenotype. Here, we describe that structural changes of teichoic acids in the cell envelope have a considerable influence on the susceptibility to vancomycin and other glycopeptides. S. aureus cells lacking D-alanine esters in teichoic acids exhibited an at least threefold-increased sensitivity to glycopeptide antibiotics. Furthermore, the autolytic activity of the D-alanine mutant was reduced compared to the wild-type, and the mutant was more susceptible to the staphylolytic enzyme lysostaphin. Vancomycin inhibited autolysis at very high concentrations but neither in the wild-type nor in the mutant was the autolytic activity influenced in the range of the MIC. Mutant cells had a considerably higher capacity to bind vancomycin.

Why are bacteria refractory to antimicrobials?

“…For instance, the intermediate vancomycin-resistance phenotype in S. aureus is due to an increased amount of non-amidated glutamine residues in the peptidoglycan. It has been suggested that the increased resistance in these strains is due to the "affinity trapping" of vancomycin in the thickened cell wall [17,18].…”

What makes resistance to methicillin heterogeneous?

“…A reduced degree of teichoic acid D-alanine substitution leads to reduced autolytic activity and, concomitantly, the methicillin MIC rises (O'Brien et al, 1995). The reduction of D-alanine esterification of teichoic acids has a negative effect on vancomycin tolerance, on the other hand (Peschel et al, 2000), which may be an indication to the observed 'incompatibility' of vancomycin and methicillin resistance in some in vitro generated mutants (Brandenberger et al, 2000;Sieradzki & Tomasz, 1997).…”

Tolerance to the Glycopeptides Vancomycin and Teicoplanin in Coagulase-Negative Staphylococci

“…Tolerance mechanisms remain elusive to this day, even if recent works on Streptococcus pneumoniae and S. aureus have suggested the involvement of impaired autolysin regulation systems (3,18) or modifications in the cell wall composition (7,17). Studies should be undertaken to explore the mechanism of the phenomenon of S. lugdunensis tolerance to glycopeptides observed in the present work and to evaluate its clinical implications.…”