Mechanisms of Fluoroquinolone Action and Resistance

doi:10.1007/978-3-642-59681-0_14

Paper

Mechanisms of Fluoroquinolone Action and Resistance

Published 2000 · K. Drlica

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Abstract

Intracellular fluoroquinolone action involves two steps. First, drug-topoisomerase-DNA complexes form in which the DNA is broken. These complexes reversibly block DNA replication and bacterial growth. Second, lethal DNA breaks are released from the complexes. Inhibitors of protein synthesis, such as chloramphenicol, block cell death and the release of DNA breaks from complexes trapped by oxolinic acid, a first generation quinolone. However, they only partially protect cells from the lethal action of fluoroquinolones, suggesting that these compounds act by the chloramphenicol-sensitive pathway and by a second pathway. Resistance to fluoroquinolones arises step-wise from mutations in the two intracellular targets, DNA gyrase and DNA topoisomerase IV. Addition of a methoxy group to N1-cyclopropyl fluoroquinolones improves bacteriostatic and bactericidal action, especially against first-step, resistant mutants. Consequently, C-8-methoxy derivatives restrict the selection of resistance by bacterial populations, a feature that has been shown for several bacterial species including clinical MDR isolates ofMycobacterium tuberculosis. Since minimum inhibitory concentration (MIC) against wild-type cells fails to accurately predict attack of resistant mutants or selection of resistance, a new parameter called mutant prevention concentration (MPC) is proposed as an additional measure of quinolone potency.

Study Snapshot

Fluoroquinolones kill bacteria by breaking their DNA, blocking growth, and preventing resistance through mutations in DNA gyrase and topoisomerase IV.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Mechanisms of Fluoroquinolone Action and Resistance

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References

Effect of Fluoroquinolone Concentration on Selection of Resistant Mutants of Mycobacterium bovis BCG andStaphylococcus aureus

Fluoroquinolone concentrations can be used to prevent the selection of resistant mutants in Mycobacterium bovis BCG and Staphylococcus aureus, with a C-8-methoxy group lowering the mutant prevention concentration.

Fluoroquinolone Action against Clinical Isolates ofMycobacterium tuberculosis: Effects of a C-8 Methoxyl Group on Survival in Liquid Media and in Human Macrophages

A C-8 methoxyl fluoroquinolone significantly enhances the bactericidal activity of quinolones against Mycobacterium tuberculosis, making it a promising antituberculosis agent.

Fluoroquinolone Action against Mycobacteria: Effects of C-8 Substituents on Growth, Survival, and Resistance

A C-8-methoxyl substituent enhances the effectiveness of fluoroquinolones against Mycobacteria, making them effective antituberculosis agents by facilitating attack on first-step gyrase mutants.

The Mechanism of Inhibition of Topoisomerase IV by Quinolone Antibacterials*

Norfloxacin causes DNA damage and cell death in bacteria by converting Topo IV into a poisonous adduct on DNA, rather than inhibiting topoisomerase activity.

Killing of Staphylococcus aureus by C-8-Methoxy Fluoroquinolones

C-8-methoxy fluoroquinolones are more effective than other derivatives in killing Staphylococcus aureus, especially when topoisomerase IV is resistant.

Citations

Effect of ciprofloxacin on methane production and anaerobic microbial community.

Ciprofloxacin (CIP) at concentrations of 0.5-50 mg/L significantly inhibits anaerobic digestion and methanogenic activity, increasing volatile fatty acids accumulation and soluble microbial products.

Adverse drug reactions: implications for the development of fluoroquinolones.

Fluoroquinolone antibacterials have shown increased activity, but increased idiosyncratic reactions and class adverse drug reactions have limited their development and use.

Comparative in vitro activity of moxifloxacin by E-test against Streptococcus pyogenes.

Moxifloxacin shows potential as a therapeutic option for treating Streptococcus pyogenes infections when penicillin cannot be used or when macrolide resistance is a local issue.

MOXIFLOXACIN (AVELOX): AN 8‐METHOXYQUINOLONE ANTIBACTERIAL WITH ENHANCED POTENCY

Moxifloxacin (AVELOX) is a novel oral antibiotic with enhanced potency against Gram-positive pathogens, particularly Streptococcus pneumoniae, and is rapidly establishing clinical acceptance and acceptance in the US.