A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacy.
Candidate antibacterials are usually identified on the basis of their in vitro activity. However, the apparent inhibitory activity of new leads can be misleading because most culture media do not reproduce an environment relevant to infection in vivo. In this study, while screening for novel anti-tuberculars, we uncovered how carbon metabolism can affect antimicrobial activity. Novel pyrimidine-imidazoles (PIs) were identified in a whole-cell screen against Mycobacterium tuberculosis. Lead optimization generated in vitro potent derivatives with desirable pharmacokinetic properties, yet without in vivo efficacy. Mechanism of action studies linked the PI activity to glycerol metabolism, which is not relevant for M. tuberculosis during infection. PIs induced self-poisoning of M. tuberculosis by promoting the accumulation of glycerol phosphate and rapid ATP depletion. This study underlines the importance of understanding central bacterial metabolism in vivo and of developing predictive in vitro culture conditions as a prerequisite for the rational discovery of new antibiotics.
Novartis Institute for Tropical Diseases, #05-01 Chromos, Singapore 138670, Singapore. kevin.pethe@novartis.com
Kevin
K
Pethe
Patricia C
PC
Sequeira
Sanjay
S
Agarwalla
Kyu
K
Rhee
Kelli
K
Kuhen
Wai Yee
WY
Phong
Viral
V
Patel
David
D
Beer
John R
JR
Walker
Jeyaraj
J
Duraiswamy
Jan
J
Jiricek
Thomas H
TH
Keller
Arnab
A
Chatterjee
Mai Ping
MP
Tan
Manjunatha
M
Ujjini
Srinivasa P S
SP
Rao
Luis
L
Camacho
Pablo
P
Bifani
Puiying A
PA
Mak
Ida
I
Ma
S Whitney
SW
Barnes
Zhong
Z
Chen
David
D
Plouffe
Pamela
P
Thayalan
Seow Hwee
SH
Ng
Melvin
M
Au
Boon Heng
BH
Lee
Bee Huat
BH
Tan
Sindhu
S
Ravindran
Mahesh
M
Nanjundappa
Xiuhua
X
Lin
Anne
A
Goh
Suresh B
SB
Lakshminarayana
Carolyn
C
Shoen
Michael
M
Cynamon
Barry
B
Kreiswirth
Veronique
V
Dartois
Eric C
EC
Peters
Richard
R
Glynne
Sydney
S
Brenner
Thomas
T
Dick
D000255:Adenosine Triphosphate / Q000378:metabolism; D000995:Antitubercular Agents / Q000494:pharmacology; D005994:Glycerophosphates / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D008954:Models, Biological; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism*
D000995:Antitubercular Agents; D005994:Glycerophosphates; D007093:Imidazoles; D000255:Adenosine Triphosphate