ABSTRACT
The antibacterial properties of novel quinoline-indole (QI) agents were examined. QI agents demonstrated potent bactericidal activities against Staphylococcus aureus, killing by lytic and nonlytic mechanisms. S. aureus mutants resistant to a lytic QI agent (SEP 155342) and a nonlytic QI agent (SEP 118843) arose at frequencies of 1.4 x 10(-9) and 1.2 x 10(-8), respectively, by selection at four times the MICs. Mutants resistant to QI agent SEP 155342 were unstable, but mutants resistant to QI agent SEP 118843 displayed stable resistance. Mutants resistant to QI agent SEP 118843 were not cross resistant to other inhibitors, including QI agent SEP 155342. Addition of QI agents SEP 118843 and SEP 155342 at four times the MIC caused nonspecific inhibition of several macromolecular biosynthetic pathways in S. aureus. Within 10 min, QI agents SEP 118843 and SEP 155342 both interfered with bacterial membrane integrity, as measured by uptake of propidium iodide. Agents from the two classes of the QI agents probably kill staphylococci by separate mechanisms which, nevertheless, both involve interference with cytoplasmic membrane function. Precise structure-activity relationships for the division of QI agents into two classes could not be determined. However, lytic activity was often associated with substitution of a basic amine at position 4 of the quinoline nucleus, whereas compounds with nonlytic activity usually contained an aromatic ring with or without a methoxy substituent at position 4. Nonlytic QI agents such as SEP 118843 may possess selective activity against the prokaryotic membrane since this compound failed to lyse mouse erythrocytes when it was added at a concentration equivalent to four times the MIC for S. aureus.
Subject(s)
Anti-Bacterial Agents/pharmacology , Escherichia coli/drug effects , Indoles/pharmacology , Quinolines/pharmacology , Staphylococcus aureus/drug effects , Animals , Cell Membrane/drug effects , Hemolysis/drug effects , Mice , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
Novel antibacterials agents, 2-(1H-indol-3-yl)tetrahydroquinolines, were prepared using hetero Diels-Alder chemistry and found to be effective in vitro against methicillin-resistant Staphylococcus aureus (MRSA). A structure-activity relationship (SAR) study was conducted to determine the important features of this series and to increase the potency of these compounds. Compounds were prepared that had minimum inhibitory concentrations (MIC's) < 1.0 microg/mL against MRSA, but had no activity versus vancomycin-resistant Enterococcus (VRE).
