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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 ؋ 10 ؊9 and 1.2 ؋ 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.Resistance to antibiotics is a major problem in the management of infections caused by gram-positive bacteria (9, 21, 31). The situation is particularly critical for treatment of infections caused by Staphylococcus aureus, in which methicillin-resistant (MRSA) and glycopeptide intermediate-resistant (GISA) strains have emerged; these strains are also frequently resistant to multiple classes of antibiotics (27,45). The recent report of an MRSA isolate resistant to the new oxazolidinone antimicrobial linezolid (46) is a further disturbing trend in the evolution of antimicrobial resistance in staphylococci. New approaches are therefore required to combat staphylococcal infections (24).Several new strategies to control staphylococcal infections have been considered in recent years. These include the use of antibiotic combinations (8,36,49), the development of new members of existing antibiotic classes (5,15,16,24,27), and the introduction of novel agents (28,44). Novel classes will be particularly advantageous since such agents, with unique modes of action, are likely to circumvent existing resistance mechanisms (3). Recently, a novel structural class of antibacterials, the quinoline-indole (QI) agents, was discovered in a library of compounds generated by combinatorial methods (19). None of the compou...

30 min under nitrogen, a solution of nitroethylene10 (219 mg, 3 mmol) in dry xylene (1 mL) was added, and then the resultant mixture was heated at 100 °C for 4 h with stirring. The reaction mixture was worked up as usual to give an oil, which showed no formyl signals in the NMR spectrum. The crude product was purified by silica gel thick

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