Start Date

2019

Description

Bacterial resistance to antibiotics is a growing public health threat. Each year, ~2 million infections and 23,000 deaths are caused by antibiotic resistance in the US. 1 Agents targeting the essential bacterial type II topoisomerases DNA gyrase and topoisomerase IV, as exemplified by the fluoroquinolones (FQs), have been shown to be useful antibiotics. FQs such as ciprofloxacin, moxifloxacin, and levofloxacin, to name a few, are broadspectrum antibacterial agents that have been in clinical use since the 1980's. Unfortunately, heavy use of the FQs has inevitably led to the development of FQresistant pathogens. 2 A gyrase inhibitor lead compound called QPT-1 has been shown to be active against multidrug-resistant bacteria,3 including ciprofloxacin-resistant strains of Staphylococcus aureus. This is apparently because QPT1 engages in unique binding interactions with the GyrB subunit of gyrase, in contrast with FQs such as moxifloxacin, which only bind to GyrA

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Biochemistry Commons

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Jan 1st, 12:00 AM

Progress Toward the Synthesis of Regioisomeric Aminomethyl-Substituted QPT-1 Bacterial Topoisomerase Inhibitors

Bacterial resistance to antibiotics is a growing public health threat. Each year, ~2 million infections and 23,000 deaths are caused by antibiotic resistance in the US. 1 Agents targeting the essential bacterial type II topoisomerases DNA gyrase and topoisomerase IV, as exemplified by the fluoroquinolones (FQs), have been shown to be useful antibiotics. FQs such as ciprofloxacin, moxifloxacin, and levofloxacin, to name a few, are broadspectrum antibacterial agents that have been in clinical use since the 1980's. Unfortunately, heavy use of the FQs has inevitably led to the development of FQresistant pathogens. 2 A gyrase inhibitor lead compound called QPT-1 has been shown to be active against multidrug-resistant bacteria,3 including ciprofloxacin-resistant strains of Staphylococcus aureus. This is apparently because QPT1 engages in unique binding interactions with the GyrB subunit of gyrase, in contrast with FQs such as moxifloxacin, which only bind to GyrA