Antimicrobial activities of mefloquine and a series of related compounds

Mefloquine was found to have bactericidal activity against methicillin- and fluoroquinolone-susceptible and -resistant strains of Staphylococcus aureu s and Staphylococcus epidermidis and gentamicin- and vancomycin-resistant s trains of Enterococcus faecalis and Enterococcus faecium. The MICs were 16 mu g/ml, and the minimal bactericidal concentrations (MBCs) were 16 to 32 m u g/ml. These concentrations cannot be achieved in serum. Mefloquine was ac tive at a more achievable concentration against penicillin-susceptible and -resistant Streptococcus pneumoniae, with MICs of 0.2 to 1.5 mu g/ml, Meflo quine was not active against gram-negative bacteria and yeasts. In an attem pt to find more active derivatives, 400 mefloquine-related compounds were s elected from the chemical inventory of The Waiter Reed Army Institute of Re search, We identified a series of compounds containing a piperidine methano l group attached to pyridine, quinoline, and benzylquinoline ring systems, These had activities similar to that of mefloquine against S, pneumoniae bu t were far more active against other gram-positive bacteria (MICs for staph ylococci, 0.8 to 6.3 mu g/ml). They had activities similar to that of ampho tericin B against Candida spp, and Cryptococcus neoformans, Combinations of the compounds with gentamicin and vancomycin were additive against staphyl ococci and pneumococci, The MIC and MBC of gentamicin were decreased by fou r- to eightfold when this drug was combined with limiting dilutions of the compounds. There was no antagonism with other antimicrobial drugs. The comp ounds were rapidly bactericidal. They appear to act by disrupting cell memb ranes. Combinations of the compounds with aminoglycoside antibiotics may ha ve potential for therapeutic use.