Suppression of beta-lactam antibiotic resistance in a methicillin- resistant Staphylococcus aureus through synergic action of early cell wall inhibitors and some other antibiotics

Abstract

We tested the effect of a number of mechanistically distinct antibacterial agents on the expression of methicillin resistance in a highly and homogeneously resistant strain of methicillin-resistant Staphylococcus aureus. The antibiotics, used at 0.25 x MIC, included inhibitors of early steps in peptidoglycan synthesis (fosfomycin, beta-chloro-D-alanine, D-cycloserine); bacitracin; teicoplanin and vancomycin; beta-lactam inhibitors chosen on the basis of their relatively selective affinities for penicillin-binding proteins 1, 2, 3 and 4 of S. aureus (imipenem, cefotaxime, cephradine and cefoxitin); compounds that inhibit various steps in protein synthesis (tetracycline, chloramphenicol, gentamicin, erythromycin and quinupristin/dalfopristin) and an inhibitor of DNA gyrase (temafloxacin). All inhibitors of early cell wall synthesis caused reduction of methicillin resistance and change from the homogeneous to the heterogeneous methicillin-resistant phenotype. Similar effects were obtained with only cephradine out of the four beta-lactams tested, and with erythromycin and quinupristin/dalfopristin as well. The other inhibitors of protein synthesis and DNA gyrase had no effect.

Quinupristin-Dalfopristin Combined with β-Lactams for Treatment of Experimental Endocarditis Due to Staphylococcus aureus Constitutively Resistant to Macrolide-Lincosamide-Streptogramin B Antibiotics

“…This bacteriostatic synergism was in accordance with the FIC indices ( Fig. 1) and was also supported by a recent report that indicated that non-cell wall inhibitors, including Q-D, could affect the expression of ␤-lactam resistance by MRSA (26).…”

Inhibition of cell wall turnover and autolysis by vancomycin in a highly vancomycin-resistant mutant of Staphylococcus aureus

“…The isolation of mutant VM was prompted by an accidental observation made during experiments testing the effect of sub-MIC levels of various cell wall synthesis inhibitors on the expression of methicillin resistance in the highly and homogeneously methicillin-resistant strain S. aureus COL (36). Vancomycin included at one-quarter of the MIC in the agar plates with the various concentrations of methicillin was found to reduce the homogeneous methicillin MIC for strain COL from 800 g/ml to a heterogeneous 25 to 50 g/ml (Fig.…”

Synergy of Daptomycin with Oxacillin and Other β-Lactams against Methicillin-Resistant Staphylococcus aureus

“…A recent study has shown that membrane depolarization and potassium leakage correlate well with decreased viability at concentrations above the daptomycin MIC (14). Sieradzki and Tomasz found that inhibitors of the early stages of peptidoglycan synthesis (e.g., fosfomycin, ␤-chloro-D-alanine, and D-cycloserine) markedly decreased the MIC of methicillin for the COL strain of MRSA from Ն800 g/ml to as low as 6 to 50 g/ml depending on the specific second antibiotic studied (13). They proposed that inhibition of the early stages of peptidoglycan synthesis resulted in the production of altered peptidoglycan precursors, which led to decreased effectiveness of penicillin binding protein 2Ј in cross-linking peptidoglycan.…”