This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Oliva, B. Articles by Chopra, I. Search for Related Content PubMed PubMed Citation Articles by Oliva, B. Articles by Chopra, I.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, February 2003, p. 458-466, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.458-466.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Biological Properties of Novel Antistaphylococcal Quinoline-Indole Agents

Brunello Oliva,¹ Keith Miller,² Nico Caggiano,² Alexander J. O'Neill,² Gregory D. Cuny,^3, Michael Z. Hoemann,^3, James R. Hauske,³ and Ian Chopra^2*

Department of Experimental Medicine, University of L'Aquila, Coppito-67100, L'Aquila, Italy,¹ Antimicrobial Research Centre and Division of Microbiology, School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom,² Sepracor Inc., Marlborough, Massachusetts 01752³

Received 28 May 2002/ Returned for modification 25 August 2002/ Accepted 31 October 2002

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.

Present address: Laboratory for Drug Discovery, Harvard Center for Neurodegeneration and Repair, Cambridge, MA 02139.

Present address: Biogen Inc., Cambridge, MA 02142.

This article has been cited by other articles:

• Hobbs, J. K., Miller, K., O'Neill, A. J., Chopra, I. (2008). Consequences of daptomycin-mediated membrane damage in Staphylococcus aureus. J Antimicrob Chemother 0: dkn321v1-6 [Abstract] [Full Text]  
• O'Neill, A. J., Miller, K., Oliva, B., Chopra, I. (2004). Comparison of assays for detection of agents causing membrane damage in Staphylococcus aureus. J Antimicrob Chemother 54: 1127-1129 [Abstract] [Full Text]  
• Hurdle, J. G., O'Neill, A. J., Chopra, I. (2004). Anti-staphylococcal activity of indolmycin, a potential topical agent for control of staphylococcal infections. J Antimicrob Chemother 54: 549-552 [Abstract] [Full Text]  
• Stubbings, W. J., Bostock, J. M., Ingham, E., Chopra, I. (2004). Assessment of a microplate method for determining the post-antibiotic effect in Staphylococcus aureus and Escherichia coli. J Antimicrob Chemother 54: 139-143 [Abstract] [Full Text]  
• Oliva, B., O'Neill, A. J., Miller, K., Stubbings, W., Chopra, I. (2004). Anti-staphylococcal activity and mode of action of clofazimine. J Antimicrob Chemother 53: 435-440 [Abstract] [Full Text]