Related Experiment Video

Updated: Jul 31, 2026

Inducing a Site Specific Replication Blockage in E. coli Using a Fluorescent Repressor Operator System
11:19

Inducing a Site Specific Replication Blockage in E. coli Using a Fluorescent Repressor Operator System

Published on: August 21, 2016

DNA topoisomerase targets of the fluoroquinolones: a strategy for avoiding bacterial resistance

X Zhao1, C Xu, J Domagala

  • 1Public Health Research Institute, 455 First Avenue, New York, NY 10016, USA.

Proceedings of the National Academy of Sciences of the United States of America
|February 12, 1998
PubMed

Insights

New C8-methoxyl fluoroquinolones require two mutations for bacterial resistance, preventing the emergence of resistant strains. This discovery offers insights into fluoroquinolone action and the development of novel antibacterial agents.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Drug Discovery

Background:

  • Fluoroquinolones are crucial antibacterial agents targeting bacterial DNA gyrase and topoisomerase IV.
  • Bacterial resistance to fluoroquinolones can arise through stepwise accumulation of mutations in these target enzymes.
  • Developing new fluoroquinolones that necessitate multiple mutations for resistance is a key strategy to combat antibacterial resistance.

Purpose of the Study:

  • To identify novel fluoroquinolone compounds that require the acquisition of two specific mutations for bacterial resistance.
  • To investigate the role of the C8-methoxyl group in the mechanism of action and resistance development of fluoroquinolones.

Main Methods:

  • Testing fluoroquinolone compounds for their ability to kill bacterial strains with pre-existing resistance mutations.
  • Comparing the emergence of resistant mutants in wild-type and mutant bacterial strains treated with C8-methoxyl fluoroquinolones and control compounds.
  • Evaluating the antibacterial efficacy of C8-methoxyl fluoroquinolones in terms of growth inhibition.

Main Results:

  • C8-methoxyl fluoroquinolones were particularly lethal to bacteria with a moderately resistant gyrase mutation.
  • Wild-type bacteria treated with C8-methoxyl fluoroquinolones did not produce resistant mutants, unlike control compounds.
  • The C8-methoxyl group appears to stimulate the release of lethal double-strand DNA breaks, a key event in fluoroquinolone action.

Conclusions:

  • C8-methoxyl fluoroquinolones necessitate two distinct topoisomerase mutations for resistance to emerge, significantly reducing the likelihood of resistance development.
  • The C8-methoxyl group plays a critical role in enhancing the lethal effects of fluoroquinolones, likely by promoting DNA breaks.
  • Understanding this mechanism can guide the development of next-generation fluoroquinolones with improved efficacy and reduced resistance potential.

More Related Videos

Visualization of Bacterial Resistance using Fluorescent Antibiotic Probes08:23

Visualization of Bacterial Resistance using Fluorescent Antibiotic Probes

Published on: March 2, 2020

Fission Yeast as a Platform for Antibacterial Drug Screens Targeting Bacterial Cytoskeleton Proteins05:57

Fission Yeast as a Platform for Antibacterial Drug Screens Targeting Bacterial Cytoskeleton Proteins

Published on: April 26, 2024

Related Concept Videos

DNA Topoisomerases02:02

DNA Topoisomerases

Topoisomerases are enzymes that relax overwound DNA molecules during various cell processes, including DNA replication and transcription. These enzymes regulate positive and negative DNA supercoiling without changing the nucleotide sequence. DNA overwinding in a clockwise direction results in positively supercoiled DNA, whereas underwinding in a counterclockwise direction produces negatively supercoiled DNA.
Types and Mechanism of action
Topoisomerases are divided into two main types.  Type I...
Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase

Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
Mechanism of Antibiotic Resistance in MRSA01:25

Mechanism of Antibiotic Resistance in MRSA

Antibiotic resistance in bacteria arises when microorganisms evolve the ability to withstand drugs designed to kill them or inhibit their growth, rendering once-effective treatments useless. This phenomenon, driven by genetic change and selection under antibiotic exposure, poses a profound threat to modern medicine. Mechanisms include drug-inactivating enzymes (e.g., β-lactamases), efflux pumps that eject antibiotics, mutations altering antibiotic targets, decreased drug uptake, and acquisition...
Inhibitors of Bacterial Protein Synthesis01:25

Inhibitors of Bacterial Protein Synthesis

Aminoglycosides constitute a highly potent class of bactericidal antibiotics that exert their antimicrobial effects by targeting the bacterial ribosome, specifically disrupting protein synthesis. These polycationic molecules consist of amino-modified sugars linked via glycosidic bonds to an aminocyclitol core such as 2-deoxystreptamine or streptamine. Their strong positive charges facilitate tight binding to the negatively charged phosphate backbone of ribosomal RNA (rRNA), primarily at the 16S...
Inhibitors of Bacterial DNA Synthesis01:28

Inhibitors of Bacterial DNA Synthesis

Bacterial pathogens depend on precise and efficient DNA replication to sustain infection. Two type II topoisomerases—DNA gyrase and topoisomerase IV—are critical to this process, as they resolve DNA supercoiling and unlink chromosomes during replication. Fluoroquinolones, synthetic derivatives of quinolones, exploit this mechanism by stabilizing the transient DNA–enzyme cleavage complex, preventing strand religation, and causing lethal double-strand breaks. These antibiotics are selectively...