Identification and characterization of novel inhibitors of mPTPB, an essential virulent phosphatase from Mycobacterium tuberculosis.
Mycobacterium protein tyrosine phosphatase B (mPTPB) is an essential virulence factor required for Mycobacterium tuberculosis (Mtb) survival in host macrophages. Consequently, mPTPB represents an exciting new target with a completely novel mechanism of action. We screened a library of 7,500 compounds against mPTPB and identified several 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide and piperazinyl-thiophenyl-ethyl-oxalamide derivatives as two distinct classes of mPTPB inhibitors. We showed that both classes of inhibitors are capable of blocking the mPTPB-mediated ERK1/2 inactivation. We further demonstrated that both classes of mPTPB inhibitors are effective in inhibiting the growth of Mtb in macrophages. Thus, improvement of the lead compounds may produce a novel class of anti-TB agents.
Chemical Genomics Core Facility, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46202.
Lan
L
Chen
Bo
B
Zhou
Sheng
S
Zhang
Li
L
Wu
Yuehong
Y
Wang
Scott G
SG
Franzblau
Zhong-Yin
ZY
Zhang