Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents.
Protein tyrosine phosphatases are often exploited and subverted by pathogenic bacteria to cause human diseases. The tyrosine phosphatase mPTPB from Mycobacterium tuberculosis is an essential virulence factor that is secreted by the bacterium into the cytoplasm of macrophages, where it mediates mycobacterial survival in the host. Consequently, there is considerable interest in understanding the mechanism by which mPTPB evades the host immune responses, and in developing potent and selective mPTPB inhibitors as unique antituberculosis (antiTB) agents. We uncovered that mPTPB subverts the innate immune responses by blocking the ERK1/2 and p38 mediated IL-6 production and promoting host cell survival by activating the Akt pathway. We identified a potent and selective mPTPB inhibitor I-A09 with highly efficacious cellular activity, from a combinatorial library of bidentate benzofuran salicylic acid derivatives assembled by click chemistry. We demonstrated that inhibition of mPTPB with I-A09 in macrophages reverses the altered host immune responses induced by the bacterial phosphatase and prevents TB growth in host cells. The results provide the necessary proof-of-principle data to support the notion that specific inhibitors of the mPTPB may serve as effective antiTB therapeutics.
Zhou
Bo
B
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
He
Yantao
Y
Zhang
Xian
X
Xu
Jie
J
Luo
Yong
Y
Wang
Yuehong
Y
Franzblau
Scott G
SG
Yang
Zhenyun
Z
Chan
Rebecca J
RJ
Liu
Yan
Y
Zheng
Jianyu
J
Zhang
Zhong-Yin
ZY
D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D054884:Host-Pathogen Interactions; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007700:Kinetics; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology / Q000502:physiology; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014376:Tuberculosis / Q000382:microbiology / Q000517:prevention & control
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D001572:Benzofurans; D004791:Enzyme Inhibitors; C549037:I-A09 compound; C414465:MptpA protein, Mycobacterium tuberculosis; D014230:Triazoles; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases