Epiroprim (EPM; Ro 11-8958) is a new selective inhibitor of microbial dihydrofolate reductase. EPM displayed excellent activity against staphylococci, enterococci, pneumococci, and streptococci which was considerably better than that of trimethoprim (TMP). EPM was also active against TMP-resistant strains, although the MICs were still relatively high. Its combination with dapsone (DDS) was synergistic and showed an in vitro activity superior to that of the TMP combination with sulfamethoxazole (SMZ). The EPM-DDS (ratio, 1:19) combination inhibited more than 90% of all important gram-positive pathogens at a concentration of 2 ؉ 38 g/ml. Only a few highly TMP-resistant staphylococci and enterococci were not inhibited. EPM was also more active than TMP against Moraxella catarrhalis, Neisseria meningitidis, and Bacteroides spp., but it was less active than TMP against all other gram-negative bacteria tested. Atypical mycobacteria were poorly susceptible to EPM, but the combination with DDS was synergistic and active at concentrations most probably achievable in biological fluids (MICs from 0.25 ؉ 4.75 to 4 ؉ 76 g/ml). EPM and the EPM-DDS combination were also highly active against experimental staphylococcal infections in a mouse septicemia model. The combination EPM-DDS has previously been shown to exhibit activity in Pneumocystis carinii and Toxoplasma models and, as shown in the present study, also shows good activity against a broad range of bacteria including many strains resistant to TMP and TMP-SMZ.

The influence of various nutrient media, growth temperature, phase of growth and subinhibitory concentrations of antibiotics from various groups on the cytoplasmic membrane proteins was studied in 6 clinical S. aureus isolates; further study included the comparison of the cytoplasmic membrane proteins in antibiotic-sensitive wild-type (parent) strains with their resistant counterparts. Resistant clones could be selected with a frequency ranging from 10^-7 to 10^-8 from the parent strain at twice the MIC. The following was observed from the study of six clinical isolates: (a) there was no uniform pattern of cytoplasmic membrane proteins among the isolates; (b) during the phase of growth, the number of high-molecular-weight proteins showed a decrease according to the duration of growth; (c) the addition of 1% w/v glucose to the growth medium resulted in the loss of an approximately 75 kD protein in five of the six strains; (d) subinhibitory concentrations of various antibiotics (1/4 of the MIC) resulted in major changes of cytoplasmic membrane proteins, when the strains were exposed to oxacillin, whereas this was not the case for erythromycin, rifampicin, gentamicin, trimethoprim, fleroxacin and vancomycin; (e) the resistant clones differed from their sensitive parent strains in their cytoplasmic membrane protein patterns. The alterations were not characteristic either for the strain or for the antibiotic considered, thus suggesting an ‘unspecific’ defense mechanism characterized by individual changes of the cytoplasmic membrane proteins.

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