Targeting lipoic acid as redox and cofactor modulator in MRSA

Summary

Infections with methicillin resistant Staphylococcus aureus (MRSA) are a global problem. Besides hospital acquired MRSA, also community associated MRSA strains have emerged that cause skin and soft tissue infections but also life threatening endocarditis and pneumonia. The increasing appearance of multidrug resistant strains urgently requires novel therapeutic approaches in order to keep the drug discovery pipeline filled. This research consortium formed by research groups from Argentina, Brazil, Germany and Latvia aims to identify antibacterial compounds by targeting the lipoic acid metabolism of S. aureus utilising two different approaches: the lipoic acid salvage pathway will be addressed by suicide substrates mimicking natural substrates, resulting in generation of nonfunctional cofactors that poison all cofactor dependent enzymes. A second approach intends to identify enzyme inhibitors targeting lipoic acid biosynthesis enzymes. In order to identify and optimise molecules targeting lipoic acid salvage and biosynthesis, a rational and integrated approach has been defined utilising a set of complementary techniques (virtual screening, enzymatic and antibacterial assays, medicinal chemistry) and expertises. The results may not only validate enzymes of the lipoic acid biosynthesis and salvage pathway as attractive targets for novel therapeutic approaches, but also provide bioactive molecules for further drug development.