Article

Antimicrobial activities of mefloquine and a series of related compounds

Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.45). 05/2000; 44(4):848-52. DOI: 10.1128/AAC.44.4.848-852.2000
Source: PubMed

ABSTRACT Mefloquine was found to have bactericidal activity against methicillin- and fluoroquinolone-susceptible and -resistant strains of Staphylococcus aureus and Staphylococcus epidermidis and gentamicin- and vancomycin-resistant strains of Enterococcus faecalis and Enterococcus faecium. The MICs were 16 microg/ml, and the minimal bactericidal concentrations (MBCs) were 16 to 32 microg/ml. These concentrations cannot be achieved in serum. Mefloquine was active at a more achievable concentration against penicillin-susceptible and -resistant Streptococcus pneumoniae, with MICs of 0.2 to 1.5 microg/ml. Mefloquine was not active against gram-negative bacteria and yeasts. In an attempt to find more active derivatives, 400 mefloquine-related compounds were selected from the chemical inventory of The Walter Reed Army Institute of Research. We identified a series of compounds containing a piperidine methanol group attached to pyridine, quinoline, and benzylquinoline ring systems. These had activities similar to that of mefloquine against S. pneumoniae but were far more active against other gram-positive bacteria (MICs for staphylococci, 0.8 to 6.3 microg/ml). They had activities similar to that of amphotericin B against Candida spp. and Cryptococcus neoformans. Combinations of the compounds with gentamicin and vancomycin were additive against staphylococci and pneumococci. The MIC and MBC of gentamicin were decreased by four- to eightfold when this drug was combined with limiting dilutions of the compounds. There was no antagonism with other antimicrobial drugs. The compounds were rapidly bactericidal. They appear to act by disrupting cell membranes. Combinations of the compounds with aminoglycoside antibiotics may have potential for therapeutic use.

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Available from: Calvin M Kunin, Apr 22, 2014
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    • "In the past few decades, most of the new drugs brought onto the market have been derivatives of older compounds. Some of them have increased activity or improved pharmacological properties against many hazardous pathogens, but can only temporarily overcome the problem of resistance (Kunin and Ellis, 2000). An example of this is the increasing resistance of Gram-positive bacteria such us staphylococci to known bactericides (Diekema et al., 2001; Kim et al., 2004; Appelbaum and Jacobs, 2005). "
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    • "In the past few decades, most of the new drugs brought onto the market have been derivatives of older compounds. Some of them have increased activity or improved pharmacological properties against many hazardous pathogens, but can only temporarily overcome the problem of resistance (Kunin and Ellis, 2000). An example of this is the increasing resistance of Gram-positive bacteria such us staphylococci to known bactericides (Diekema et al., 2001; Kim et al., 2004; Appelbaum and Jacobs, 2005). "
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    • "However, the inhibition by optochin and mefloquine, specific inhibitors of the pneumococcal F 0 F 1 H 1 -ATPase, was only 15% and 23% respectively (data not shown). As it has been shown that the amino alcohol antimalarials are both able to inhibit growth (Kunin and Ellis, 2000) and cross the E. coli membranes (Nissani and Ginsburgh, 1989), these results suggested that the overproduced subunits of the S. pneumoniae ATPase were not correctly assembled inside the E. coli membrane, possibly because the capacity of the membrane was exceeded. "
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