Journal Article

Mechanisms of Action of Antimicrobials: Focus on Fluoroquinolones

David C. Hooper

in Clinical Infectious Diseases

Published on behalf of Infectious Diseases Society of America

Volume 32, issue Supplement_1, pages S9-S15
Published in print March 2001 | ISSN: 1058-4838
Published online March 2001 | e-ISSN: 1537-6591 | DOI: http://dx.doi.org/10.1086/319370
Mechanisms of Action of Antimicrobials: Focus on Fluoroquinolones

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Five bacterial targets have been exploited in the development of antimicrobial drugs: cell wall synthesis, protein synthesis, ribonucleic acid synthesis, deoxyribonucleic acid (DNA) synthesis, and intermediary metabolism. Because resistance to drugs that interact with these targets is widespread, new antimicrobials and an understanding of their mechanisms of action are vital. The fluoroquinolones are the only direct inhibitors of DNA synthesis; by binding to the enzyme-DNA complex, they stabilize DNA strand breaks created by DNA gyrase and topoisomerase IV. Ternary complexes of drug, enzyme, and DNA block progress of the replication fork. Cytotoxicity of fluoroquinolones is likely a 2-step process involving (1) conversion of the topoisomerase-quinolone-DNA complex to an irreversible form and (2) generation of a double-strand break by denaturation of the topoisomerase. The molecular factors necessary for the transition from step 1 to step 2 remain unclear, but downstream pathways for cell death may overlap with those used by other bactericidal antimicrobials. Studies of fluoroquinolone-resistant mutants and purified topoisomerases indicate that many quinolones have differing activities against the two targets. Drugs with similar activities against both targets may prove less likely to select de novo resistance.

Journal Article.  5165 words.  Illustrated.

Subjects: Infectious Diseases ; Immunology ; Public Health and Epidemiology ; Microbiology

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