Start Date
2018
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 Developing antibiotics for treating Gram-negative bacteria is especially challenging because they utilize two membranes, an outer membrane that is hydrophilic, and an inner membrane that is lipophilic, features that make cellular entry a challenge. These bacteria also have antibiotic de-activating enzymes and RND efflux pumps that work to remove the antibiotics from the cell. These features make targeting of Gram-negative organisms very difficult. Agents targeting the essential bacterial type II topoisomerases DNA gyrase and topoisomerase IV have been shown to be useful antibiotics, as exemplified by the fluoroquinolones (FQs). 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 FQ-resistant pathogens.2 A lead compound called QPT-1 has been shown to be active against quinolone-resistant bacteria,3 with low MIC values (MIC90 = 0.5 mg/mL), including ciprofloxacinresistant strains of Staphylococcus aureus. This is apparently because QPT-1 engages in unique binding interactions with the GyrB subunit of gyrase, in contrast with FQs such as moxifloxacin, which only bind to GyrA
Recommended Citation
Scoville, Riley and Barbachyn, Michael, "Progress Toward the Synthesis of Aminomethyl-Substituted QPT-1 Bacterial Topoisomerase Inhibitors" (2018). Summer Research. 10.
https://digitalcommons.calvin.edu/summer_research/2018/Posters/10
Included in
Progress Toward the Synthesis of 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 Developing antibiotics for treating Gram-negative bacteria is especially challenging because they utilize two membranes, an outer membrane that is hydrophilic, and an inner membrane that is lipophilic, features that make cellular entry a challenge. These bacteria also have antibiotic de-activating enzymes and RND efflux pumps that work to remove the antibiotics from the cell. These features make targeting of Gram-negative organisms very difficult. Agents targeting the essential bacterial type II topoisomerases DNA gyrase and topoisomerase IV have been shown to be useful antibiotics, as exemplified by the fluoroquinolones (FQs). 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 FQ-resistant pathogens.2 A lead compound called QPT-1 has been shown to be active against quinolone-resistant bacteria,3 with low MIC values (MIC90 = 0.5 mg/mL), including ciprofloxacinresistant strains of Staphylococcus aureus. This is apparently because QPT-1 engages in unique binding interactions with the GyrB subunit of gyrase, in contrast with FQs such as moxifloxacin, which only bind to GyrA