Fluoroquinolones and Other Antibiotics

Fluoroquinolones are broad-spectrum antibacterials that kill bacteria by inhibiting the enzymes that manage DNA topology — DNA gyrase and topoisomerase IV. This entry uses the fluoroquinolones as its anchor and also surveys other antibacterial classes that fall outside the cell-wall and ribosomal groups, including glycopeptides, sulfonamides and trimethoprim, and the polymyxins.

Definition

Fluoroquinolones are synthetic, fluorinated quinolone antibacterials that inhibit bacterial type II topoisomerases (DNA gyrase and topoisomerase IV), blocking DNA replication and inducing lethal double-strand breaks.

Scope

The entry covers the mechanism of fluoroquinolones, their principal resistance routes, and a brief orientation to several additional classes grouped by their distinct targets. It is a reference and educational topic; it offers no dosing, regimen, or individual treatment guidance, and notes safety considerations only at the level of class pharmacology.

Core questions

• How do fluoroquinolones inhibit DNA gyrase and topoisomerase IV?
• What are the main mechanisms of fluoroquinolone resistance?
• What other antibacterial classes target processes outside the cell wall and ribosome?
• How do glycopeptides, folate-pathway inhibitors, and polymyxins differ in target?

Key concepts

• DNA gyrase and topoisomerase IV
• Quinolone resistance-determining region (QRDR)
• Target-site mutations in gyrA and parC
• Plasmid-mediated quinolone resistance (qnr genes)
• Glycopeptides (vancomycin) and D-Ala-D-Ala binding
• Sulfonamides and trimethoprim (folate-pathway inhibition)
• Polymyxins and the outer membrane

Mechanisms

Fluoroquinolones bind the complex of DNA and bacterial type II topoisomerases — DNA gyrase (encoded by gyrA/gyrB) and topoisomerase IV (parC/parE) — trapping cleaved DNA intermediates and converting the enzymes into agents of double-strand breakage, which is bactericidal (Hooper & Jacoby, 2016). Resistance arises chiefly from point mutations in the quinolone resistance-determining region of gyrA or parC, from reduced drug accumulation via efflux and altered porins, and from plasmid-mediated qnr genes that protect the target (Ruiz, 2003; Hooper & Jacoby, 2016). Among the other classes surveyed here, glycopeptides such as vancomycin bind the D-alanyl-D-alanine terminus of peptidoglycan precursors to block cell-wall synthesis (Rybak et al., 2009); sulfonamides and trimethoprim inhibit sequential steps of bacterial folate synthesis; and polymyxins disrupt the Gram-negative outer membrane.

Clinical relevance

Fluoroquinolones and the other classes summarised here are important parts of the antibacterial armamentarium, and their distinct targets and resistance mechanisms inform laboratory testing and stewardship. Class-level safety signals, such as the adverse effects associated with fluoroquinolones, are part of why their use is weighed carefully (Owens & Ambrose, 2005). This entry is educational and does not provide dosing or individualised treatment advice.

Epidemiology

Fluoroquinolone resistance has risen across many Gram-negative and Gram-positive pathogens, driven by chromosomal target mutations and the spread of plasmid-mediated qnr determinants, which can facilitate the stepwise emergence of high-level resistance (Ruiz, 2003; Hooper & Jacoby, 2016).

History

The quinolones began with nalidixic acid in the 1960s; fluorination and further substitution in the 1980s produced the fluoroquinolones, with markedly broader spectrum and improved tissue penetration. Recognition of class-associated safety concerns and the steady accumulation of resistance determinants later tempered their role (Owens & Ambrose, 2005; Hooper & Jacoby, 2016).

Key figures

• David C. Hooper
• George A. Jacoby
• Joaquim Ruiz

Seminal works

• hooper-jacoby-2016
• ruiz-2003

Frequently asked questions

What do fluoroquinolones target inside the bacterium?

They inhibit the bacterial type II topoisomerases DNA gyrase and topoisomerase IV, which manage DNA supercoiling and separation; trapping these enzymes on DNA produces lethal double-strand breaks.

How do bacteria become resistant to fluoroquinolones?

Most commonly through mutations in the quinolone resistance-determining region of gyrA or parC that lower drug binding, together with increased efflux, reduced uptake, and plasmid-borne qnr protection genes.