Editors' ChoicePharmacology

Antibiotics Target Akt

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Science's STKE  04 Dec 2007:
Vol. 2007, Issue 415, pp. tw441
DOI: 10.1126/stke.4152007tw441

Bacteria use various strategies to avoid destruction by the host cell, and many of these involve modifying intracellular signaling pathways to allow bacterial survival and promote bacterial replication. For example, Salmonella activates protein kinase A (PKA) and Akt (also known as protein kinase B), which may allow bacterial survival by altering the actin cytoskeleton and inhibiting fusion of phagosomes with lysosomes (the bacteria reside in phagosomes). Based on this information, Kuijl et al. tested a panel of kinase inhibitors for the ability to inhibit Salmonella typhimurium growth in the human breast cancer cell line MCF7. H-89, which inhibits PKA and structurally related kinases, inhibited bacterial growth without compromising host cell viability. However, two other specific PKA inhibitors failed to inhibit bacterial growth, which suggests that the target of H-89 in this antibiotic effect was not PKA. H-89 and two related compounds, ETB067 and ETB275, also inhibited growth of two myobacterial strains in human macrophages, suggesting that these pathogens rely on similar host cell kinases for survival. Using a siRNA screen targeting the human kinome and 121 kinase-associated or regulatory proteins, the authors identified 11 kinases and 3 kinase-associated proteins that when knocked down inhibited S. typhimurium growth. One of these was Akt1; none of these was PKA. Akt1 is also inhibited by H-89 because of the structural similarity of the ATP-binding site with that of PKA. Indeed, an inhibitor selective for Akt1 and Akt2 also inhibited S. typhimurium and M. smegmatis growth in macrophages and MCF7 cells; however, inhibition of both Akt isoforms ultimately caused apoptosis. Treatment of S. typhimurium-infected mice with ETB067 prolonged mouse survival without any apparent effect on viability and without causing tissue damage. Akt is activated as a consequence of the action of the bacterial protein SopB, which has phosphoinositide phosphatase activity. The regulation of the activity of three guanosine triphosphatases (GTPases), RhoA, Rac1, and Rab14, by Akt appears to be an important mechanism by which pathogen activation of Akt contributes to pathogen survival and replication. In the presence of the Akt inhibitor, a constitutively active form of the kinase PAK4, which is upstream of RhoA and Rac1 and is involved in regulation of the actin cytoskeleton, partially rescued intracellular growth of S. typhimurium. In addition, the active form of Rab14, which is also stimulated in response to Akt, remained associated with phagosomes longer in infected cells than in noninfected cells, thereby inhibiting lysosomal fusion by an unknown mechanism. Overexpressing Rab14 or knocking down its GTPase-activating protein AS160 partially reversed S. typhimurium growth in Akt-inhibited cells. Thus, the authors suggest that Akt1 appears to be an attractive target for antibiotic development.

C. Kuijl, N. D. L. Savage, M. Marsman, A. W. Tuin, L. Janssen, D. A. Egan, M. Ketema, R. van den Nieuwendijk, S. J. F. van den Eeden, A. Geluk, A. Poot, G. van der Marel, R. L. Beijersbergen, H. Overkleeft, T. H. M. Ottenhoff, J. Neefjes, Intracellular bacterial growth is controlled by a kinase network around PKB/AKT1. Nature 450, 725-730 (2007). [PubMed]

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