Anti-virulence strategy against Brucella suis: synthesis, biological evaluation and molecular modeling of selective histidinol dehydrogenase inhibitors.

In the facultative intracellular pathogen Brucella suis, histidinol dehydrogenase (HDH) activity, catalyzing the last step in histidine biosynthesis, is essential for intramacrophagic replication. The inhibition of this virulence factor by substituted benzylic ketones was a proof of concept that disarming bacteria leads to inhibition of intracellular bacterial growth in macrophage infection. This work describes the design, synthesis and evaluation of 19 new potential HDH inhibitors, using a combination of classical approaches and docking studies.

Carbonic anhydrase activators: activation of human isozymes I, II and IX with phenylsulfonylhydrazido l-histidine derivatives.

Activation of the human carbonic anhydrase (CA, EC 4.2.1.

Brucella suis histidinol dehydrogenase: synthesis and inhibition studies of substituted N-L-histidinylphenylsulfonyl hydrazide.

Histidinol dehydrogenase (HDH, EC EC1.1.1.

Targeting of the Brucella suis virulence factor histidinol dehydrogenase by histidinol analogues results in inhibition of intramacrophagic multiplication of the pathogen.

Brucella suis histidinol dehydrogenase (HDH) can be efficiently targeted by substrate analogues. The growth of this pathogen in minimal medium was inhibited and the multiplication in human macrophages was totally abolished in the presence of the drugs. These effects have been shown to be correlated with the previously described inhibition of Brucella HDH activity.

Brucella suis histidinol dehydrogenase: synthesis and inhibition studies of a series of substituted benzylic ketones derived from histidine.

Brucella spp. is the causative agent of brucellosis (Malta fever), which is the most widespread zoonosis worldwide. The pathogen is capable of establishing persistent infections in humans which are extremely difficult to eradicate even with antibiotic therapy.