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

John I Manchester; Daemian D Dussault; Jonathan A Rose; P Ann Boriack-Sjodin; Maria Uria-Nickelsen; Georgine Ioannidis; Shanta Bist; Paul Fleming; Kenneth G Hull

doi:10.1016/j.bmcl.2012.05.128

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

Bioorg Med Chem Lett. 2012 Aug 1;22(15):5150-6. doi: 10.1016/j.bmcl.2012.05.128. Epub 2012 Jun 19.

Authors

John I Manchester¹, Daemian D Dussault, Jonathan A Rose, P Ann Boriack-Sjodin, Maria Uria-Nickelsen, Georgine Ioannidis, Shanta Bist, Paul Fleming, Kenneth G Hull

Affiliation

¹ Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, MA 02451, USA. [email protected]

PMID: 22814212
DOI: 10.1016/j.bmcl.2012.05.128

Abstract

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 1.56 μM. 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.

MeSH terms

Adenosine Triphosphatases / chemistry
Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry*
Anti-Bacterial Agents / pharmacology
Aza Compounds / chemistry
Bacterial Proteins / chemistry
Bacterial Proteins / metabolism
Binding Sites
Crystallography, X-Ray
DNA Gyrase / metabolism
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
Indoles / chemical synthesis
Indoles / chemistry*
Indoles / pharmacology
Methicillin-Resistant Staphylococcus aureus / drug effects
Microbial Sensitivity Tests
Protein Structure, Tertiary
Structure-Activity Relationship
Topoisomerase II Inhibitors*

Substances

Anti-Bacterial Agents
Aza Compounds
Bacterial Proteins
Enzyme Inhibitors
Indoles
Topoisomerase II Inhibitors
indole
Adenosine Triphosphatases
DNA Topoisomerase IV
DNA Gyrase