Discovery of a novel azaindole class of antibacterial agents targeting the ATPase domains of DNA gyrase and Topoisomerase IV

• Published in: Bioorganic & medicinal chemistry letters 2012-08, Vol.22 (15), p.5150-5156
• Main Authors: Manchester, John I., Dussault, Daemian D., Rose, Jonathan A., Boriack-Sjodin, P. Ann, Uria-Nickelsen, Maria, Ioannidis, Georgine, Bist, Shanta, Fleming, Paul, Hull, Kenneth G.
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases - chemistry; adenosinetriphosphatase; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial; Antibacterial agents; antibiotic resistance; antibiotics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Aza Compounds - chemistry; Azaindole; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Binding Sites; Biological and medical sciences; chemistry; Crystallography, X-Ray; DNA gyrase; DNA Gyrase - metabolism; DNA topoisomerase (ATP-hydrolysing); DNA Topoisomerase IV - antagonists & inhibitors; DNA Topoisomerase IV - metabolism; Drug Evaluation, Preclinical; Drug Resistance, Bacterial - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; growth retardation; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Medical sciences; Methicillin-Resistant Staphylococcus aureus - drug effects; Microbial Sensitivity Tests; mutation; Pharmacology. Drug treatments; Protein Structure, Tertiary; screening; Staphylococcus aureus; Structure-Activity Relationship; Structure-based design; Topoisomerase II Inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.05.128

We present the discovery and optimization of a novel series of bacterial topoisomerase inhibitors. Starting from a virtual screening hit, activity was optimized through a combination of structure-based design and physical property optimization. Synthesis of fewer than a dozen compounds was required to achieve inhibition of the growth of methicillin-resistant Staphyloccus aureus (MRSA) at compound concentrations of 1.56μM. These compounds simultaneously inhibit DNA gyrase and Topoisomerase IV at similar nanomolar concentrations, reducing the likelihood of the spontaneous occurrence of target-based mutations resulting in antibiotic resistance, an increasing threat in the treatment of serious infections.