Discovery of a novel azaindole class of antibacterial agents targeting the ATPase domains of DNA gyrase and Topoisomerase IV.
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.
Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, MA 02451, USA. john.manchester@astrazeneca.com
John I
JI
Manchester
Daemian D
DD
Dussault
Jonathan A
JA
Rose
P Ann
PA
Boriack-Sjodin
Maria
M
Uria-Nickelsen
Georgine
G
Ioannidis
Shanta
S
Bist
Paul
P
Fleming
Kenneth G
KG
Hull
D000251:Adenosine Triphosphatases / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001372:Aza Compounds / Q000737:chemistry; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D027081:DNA Gyrase / Q000378:metabolism; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D007211:Indoles; D059005:Topoisomerase II Inhibitors; C030374:indole; D000251:Adenosine Triphosphatases; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase