In vivo validation of thymidylate kinase (TMK) with a rationally designed, selective antibacterial compound.
There is an urgent need for new antibacterials that pinpoint novel targets and thereby avoid existing resistance mechanisms. We have created novel synthetic antibacterials through structure-based drug design that specifically target bacterial thymidylate kinase (TMK), a nucleotide kinase essential in the DNA synthesis pathway. A high-resolution structure shows compound TK-666 binding partly in the thymidine monophosphate substrate site, but also forming new induced-fit interactions that give picomolar affinity. TK-666 has potent, broad-spectrum Gram-positive microbiological activity (including activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus), bactericidal action with rapid killing kinetics, excellent target selectivity over the human ortholog, and low resistance rates. We demonstrate in vivo efficacy against S. aureus in a murine infected-thigh model. This work presents the first validation of TMK as a compelling antibacterial target and provides a rationale for pursuing novel clinical candidates for treating Gram-positive infections through TMK.
AstraZeneca Infection Innovative Medicines, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States. thomas.keating@astrazeneca.com
Thomas A
TA
Keating
Joseph V
JV
Newman
Nelson B
NB
Olivier
Linda G
LG
Otterson
Beth
B
Andrews
P Ann
PA
Boriack-Sjodin
John N
JN
Breen
Peter
P
Doig
Jacques
J
Dumas
Eric
E
Gangl
Oluyinka M
OM
Green
Satenig Y
SY
Guler
Martin F
MF
Hentemann
Diane
D
Joseph-McCarthy
Sameer
S
Kawatkar
Amy
A
Kutschke
James T
JT
Loch
Andrew R
AR
McKenzie
Selvi
S
Pradeepan
Swati
S
Prasad
Gabriel
G
Martínez-Botella
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D016983:Enterococcus / Q000187:drug effects / Q000201:enzymology; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000201:enzymology*; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy; D006801:Humans; D008958:Models, Molecular; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology
D000900:Anti-Bacterial Agents; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase