SYNERGY AND RESISTANCE TO SYNERGY BETWEEN BETA-LACTAM ANTIBIOTICS ANDGLYCOPEPTIDES AGAINST GLYCOPEPTIDE-RESISTANT STRAINS OF ENTEROCOCCUS-FAECIUM

A synergistic effect between vancomycin or teicoplanin and different b eta-lactam antibiotics was found for two strains of Enterococcus faeci um, EFM4 and EFM11, expressing resistance to glycopeptides and belongi ng to the VANA class. The MICs of penicillin for these two strains wer e 16 and 128 mug/ml, respectively. By using a penicillin-binding prote in (PBP) competition assay, it was shown that the affinities of PBPs f or different beta-lactam antibiotics and the MICs of these antibiotics obtained in the presence of teicoplanin correlated with the substitut ion of two high-molecular-weight PBPs for the low-molecular-weight PBP 5 as the essential target. Mutants of EFM4 and EFM11 which had lost th e synergistic effect between beta-lactams and glycopeptides were selec ted on teicoplanin plus ceftriaxone at a frequency of 10(-5) and 10(-3 ), respectively. The mechanism of the loss of synergy was explored. Fo r the mutants derived from EFM4, it was associated with a change in PB Ps, while for the mutants derived from EFM11, it was related to some u nknown change on the conjugative plasmid responsible for the glycopept ide resistance. These combined observations reflect the relationship w hich seems to exist between the new D-lactate peptidoglycan precursor, synthesized when the vancomycin resistance is expressed, and the affi nity of the different PBPs for this precursor.