Integrating chemical and genetic silencing strategies to identify host kinase-phosphatase inhibitor networks that control bacterial infection

TY - JOUR

T1 - Integrating chemical and genetic silencing strategies to identify host kinase-phosphatase inhibitor networks that control bacterial infection

AU - Albers, Harald M H G

AU - Kuijl, Coenraad

AU - Bakker, Jeroen

AU - Hendrickx, Loes

AU - Wekker, Sharida

AU - Farhou, Nadha

AU - Liu, Nora

AU - Blasco-Moreno, Bernat

AU - Scanu, Tiziana

AU - den Hertog, Jeroen

AU - Celie, Patrick

AU - Ovaa, Huib

AU - Neefjes, Jacques

PY - 2014/2/21

Y1 - 2014/2/21

N2 - Every year three million people die as a result of bacterial infections, and this number may further increase due to resistance to current antibiotics. These antibiotics target almost all essential bacterial processes, leaving only a few new targets for manipulation. The host proteome has many more potential targets for manipulation in order to control bacterial infection, as exemplified by the observation that inhibiting the host kinase Akt supports the elimination of different intracellular bacteria including Salmonella and M. tuberculosis. If host kinases are involved in the control of bacterial infections, phosphatases could be as well. Here we present an integrated small interference RNA and small molecule screen to identify host phosphatase-inhibitor combinations that control bacterial infection. We define host phosphatases inhibiting intracellular growth of Salmonella and identify corresponding inhibitors for the dual specificity phosphatases DUSP11 and 27. Pathway analysis places many kinases and phosphatases controlling bacterial infection in an integrated pathway centered around Akt. This network controls host cell metabolism, survival, and growth and bacterial survival and reflect a natural host cell response to bacterial infection. Inhibiting two enzyme classes with opposite activities-kinases and phosphatases-may be a new strategy to overcome infections by antibiotic-resistant bacteria.

AB - Every year three million people die as a result of bacterial infections, and this number may further increase due to resistance to current antibiotics. These antibiotics target almost all essential bacterial processes, leaving only a few new targets for manipulation. The host proteome has many more potential targets for manipulation in order to control bacterial infection, as exemplified by the observation that inhibiting the host kinase Akt supports the elimination of different intracellular bacteria including Salmonella and M. tuberculosis. If host kinases are involved in the control of bacterial infections, phosphatases could be as well. Here we present an integrated small interference RNA and small molecule screen to identify host phosphatase-inhibitor combinations that control bacterial infection. We define host phosphatases inhibiting intracellular growth of Salmonella and identify corresponding inhibitors for the dual specificity phosphatases DUSP11 and 27. Pathway analysis places many kinases and phosphatases controlling bacterial infection in an integrated pathway centered around Akt. This network controls host cell metabolism, survival, and growth and bacterial survival and reflect a natural host cell response to bacterial infection. Inhibiting two enzyme classes with opposite activities-kinases and phosphatases-may be a new strategy to overcome infections by antibiotic-resistant bacteria.

KW - Anti-Bacterial Agents

KW - Cell Line

KW - Dual-Specificity Phosphatases

KW - Enzyme Inhibitors

KW - Gene Silencing

KW - Host-Pathogen Interactions

KW - Humans

KW - Proto-Oncogene Proteins c-akt

KW - Salmonella Infections

KW - Salmonella typhimurium

KW - Small Molecule Libraries

U2 - 10.1021/cb400421a

DO - 10.1021/cb400421a

M3 - Article

C2 - 24274083

SN - 1552-4450

VL - 9

SP - 414

EP - 422

JO - Nature Chemical Biology

JF - Nature Chemical Biology

IS - 2

ER -