Ricerc@Sapienza

Mycobacterium tuberculosis antibiotic resistance represents an increasing threat to global public health as prevents the effective treatment of tuberculosis, one of the top 10 causes of death worldwide. Therefore, understanding how this bacterial pathogen resists the immune system and identifying novel drug targets for therapeutic intervention is crucial for the successful cure of this infectious disease.

Recently targeting bacterial respiration and ATP synthesis has received strong interest as a new strategy for combating the obligate aerobe M. tuberculosis. Our working hypothesis is that the respiratory chain endows this pathogen with the ability to successfully resist NO and related nitrosative stress produced by the host immune response during infection. Mycobacterial respiratory chain is branched and relies on two terminal oxidases, the aa3- cytochrome c oxidase, forming a supercomplex with cytochrome bcc, and the bd quinol oxidase.

Relevant to human pathophysiology, bd type oxidases are key respiratory enzymes that confer bacterial resistance to nitro-oxidative stress and promote virulence in some pathogens, including mycobacteria. Since these enzymes are found only in prokaryotes, they are of great interest as potential drug targets, particularly for combined therapeutic approaches to strengthen the bactericidal effects of antimicrobials targeting other systems.

The present project aims at studying the M. tuberculosis respiratory chain complexes to understand the role played by these enzymes within the framework of host-pathogen relationships.
Research will focus on the identification of selective inhibitors of cytochrome bd activity, on the purification of an active mycobacterial cytochrome bd, as well as on the interaction of NO with the mycobacterial bcc/ aa3 supercomplex to shed light on the reaction mechanisms and their patho-physiological relevance.