Antibacterial inhibitors of Gram-positive thymidylate kinase: structure-activity relationships and chiral preference of a new hydrophobic binding region.
Thymidylate kinase (TMK), an essential enzyme in bacterial DNA biosynthesis, is an attractive therapeutic target for the development of novel antibacterial agents, and we continue to explore TMK inhibitors with improved potency, protein binding, and pharmacokinetic potential. A structure-guided design approach was employed to exploit a previously unexplored region in Staphylococcus aureus TMK via novel interactions. These efforts produced compound 39, with 3 nM IC50 against S. aureus TMK and 2 μg/mL MIC against methicillin-resistant S. aureus (MRSA). This compound exhibits a striking inverted chiral preference for binding relative to earlier compounds and also has improved physical properties and pharmacokinetics over previously published compounds. An example of this new series was efficacious in a murine S. aureus infection model, suggesting that compounds like 39 are options for further work toward a new Gram-positive antibiotic by maintaining a balance of microbiological potency, low clearance, and low protein binding that can result in lower efficacious doses.
Infection Innovative Medicines and ‡Discovery Sciences, AstraZeneca , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Sameer P
SP
Kawatkar
Thomas A
TA
Keating
Nelson B
NB
Olivier
John N
JN
Breen
Oluyinka M
OM
Green
Satenig Y
SY
Guler
Martin F
MF
Hentemann
James T
JT
Loch
Andrew R
AR
McKenzie
Joseph V
JV
Newman
Linda G
LG
Otterson
Gabriel
G
Martínez-Botella
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D024881:Drug Resistance, Bacterial; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000201:enzymology; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010880:Piperidines; D011744:Pyrimidinones; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase