Antibacterial activities of epiroprim, a new dihydrofolate reductase inhibitor, alone and in combination with dapsone

Abstract

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.

Methicillin-Resistant Staphylococcus aureus: An Evolutionary, Epidemiologic, and Therapeutic Odyssey

“…The rifamycin rifalazil retains activity against some isolates that are resistant to rifampin [127]. Epiroprim is a dihydrofolate reductase inhibitor with activity against some trimethoprim-resistant strains of S. aureus; its combination with dapsone results in in vitro activity against S. aureus that is greater than that of TMP-SMZ [128]. Iclaprim is another dihydrofolate reductase inhibitor with activity against MRSA [129].…”

Community-acquired methicillin-resistant Staphylococcus aureus infections

“…The industry has also developed: the new rifamycin, rifazil, which retains activity against staphylococcal isolates resistant to rifampicin [87]; some new dihydrofolate reductase inhibitors such as iclaprim and epiroprim [88,89]; newer oxazolidinones such as ranbezolid [90]; newer fluoroquinolones still under investigation [91,92]; as well as cationic peptides [93] and lysostaphin [94], which possess in vitro activity both against MSSA and MRSA strains. However, clinical experience in humans is still pending.…”

Dihydrofolate Reductase as a Target for Chemotherapy in Parasites

“…3) showed promise in the treatment of Gram-positive infections and infections caused by several opportunistic protozoa [76,77]. Compound 10 also displayed …”