Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria

Area of Science:

• Medicinal Chemistry
• Microbiology
• Structural Biology

Background:

• Quinolone antibiotics are broad-spectrum agents inhibiting bacterial DNA gyrase and topoisomerase IV.
• Increasing antibiotic resistance, particularly mutations in the quinolone resistance determining region, threatens quinolone efficacy.
• There is a critical need for novel antibiotics effective against resistant bacterial strains.

Purpose of the Study:

• To discover and optimize novel 4-(aminomethyl)quinolin-2(1H)-ones as antibacterial agents.
• To evaluate the activity of these compounds against ciprofloxacin-resistant Gram-negative pathogens.
• To elucidate the mechanism of action and binding mode of the lead compound.

Main Methods:

• Synthesis and chemical optimization of 4-(aminomethyl)quinolin-2(1H)-one derivatives.
• In vitro antibacterial activity assays against a panel of Gram-negative bacteria, including resistant strains.
• X-ray crystallography to determine the binding mode of the lead compound (34) in complex with topoisomerase IV.

Main Results:

• A series of 4-(aminomethyl)quinolin-2(1H)-ones were synthesized and optimized.
• Compound 34 demonstrated potent activity against ciprofloxacin-resistant Gram-negative pathogens.
• X-ray crystallography showed that compound 34 binds to the classical quinolone binding site without interacting with resistance-conferring mutations.

Conclusions:

• 4-(aminomethyl)quinolin-2(1H)-ones represent a promising new class of antibiotics.
• Compound 34 overcomes common quinolone resistance mechanisms.
• This discovery provides a potential strategy to combat Gram-negative bacterial infections resistant to current therapies.