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.
Pethe
Kevin
K
Novartis Institute for Tropical Diseases, #05-01 Chromos, Singapore 138670, Singapore. kevin.pethe@novartis.com
Sequeira
Patricia C
PC
Agarwalla
Sanjay
S
Rhee
Kyu
K
Kuhen
Kelli
K
Phong
Wai Yee
WY
Patel
Viral
V
Beer
David
D
Walker
John R
JR
Duraiswamy
Jeyaraj
J
Jiricek
Jan
J
Keller
Thomas H
TH
Chatterjee
Arnab
A
Tan
Mai Ping
MP
Ujjini
Manjunatha
M
Rao
Srinivasa P S
SP
Camacho
Luis
L
Bifani
Pablo
P
Mak
Puiying A
PA
Ma
Ida
I
Barnes
S Whitney
SW
Chen
Zhong
Z
Plouffe
David
D
Thayalan
Pamela
P
Ng
Seow Hwee
SH
Au
Melvin
M
Lee
Boon Heng
BH
Tan
Bee Huat
BH
Ravindran
Sindhu
S
Nanjundappa
Mahesh
M
Lin
Xiuhua
X
Goh
Anne
A
Lakshminarayana
Suresh B
SB
Shoen
Carolyn
C
Cynamon
Michael
M
Kreiswirth
Barry
B
Dartois
Veronique
V
Peters
Eric C
EC
Glynne
Richard
R
Brenner
Sydney
S
Dick
Thomas
T
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