FERNANDEZ Pablo Mariano
congresos y reuniones científicas
The Ser/Thr Protein Kinase PknB, a potential Target for the Development of Novel Antibiotics Against Mycobacteria
PABLO FERNANDEZ; ANNEMARIE WEHENKEL; BRIGITTE SAINT-JOANIS; NATHALIE BARILONE; MARCO BELLINZONI; VINCENT CATHERINOT; GILLES LABESSE; MARY JACKSON; BRIGITTE GICQUEL; PEDRO ALZARI; STEWART COLE
Conferencia; Euroconference Protein Kinase Inhibitors; 2006
The receptor-like protein kinase PknB from Mycobacterium tuberculosis is encoded by the distal gene in an operon, near the chromosomal origin of replication, that is highly conserved in actinobacteria and possibly involved in cell shape and cell division control. Genes coding for a PknB-like protein kinase are also found in a large number of more distantly related Gram-positive bacteria. Here we report that the pknB gene can be disrupted by allelic replacement in M. tuberculosis and the saprophyte M. smegmatis only in the presence of a second functional copy of the gene. We also demonstrate that eukaryotic STPK inhibitors, which inactivate PknB in vitro with an IC50 in the sub-micromolar range, are able to kill M. tuberculosis H37Rv, M. smegmatis mc2155, and M. aurum A+ with minimal inhibitory concentration (MIC) in the micromolar range. Furthermore, significantly higher concentrations of these compounds are required to inhibit growth of M. smegmatis strains overexpressing PknB, suggesting that this protein kinase is the molecular target. The structure of a complex between PknB and mitoxantrone reveals that this inhibitor partially occupies the kinase adenine binding pocket, providing a framework for the design of compounds with potential therapeutic applications. These findings demonstrate that the Ser/Thr protein kinase PknB is essential to sustain mycobacterial growth and support the development of protein kinase inhibitors as new potential antituberculosis drugs.