Drugs against Multiresistant Tuberculosis
Search of New Antituberculosis Drugs Blocking Nicotinamide-Adeninedinucleotide Biosynthesis and Efficient Against Multiple Drug Resistant Tuberculosis
Tech Area / Field
- MED-DRG/Drug Discovery/Medicine
3 Approved without Funding
Institute of Immunological Engineering, Russia, Moscow reg., Lyubuchany
- US Department of Health & Human Services / National Institute of Health / National Institute of Allergy and Infectious Diseases, USA, MD, Bethesda
Project summarySpread of tuberculosis, in particular its form resistant to the first-line antitubercular drugs (MDR-TB) represents a major threat to the human population. There is urgent need to develop new drugs against Mycobacterium tuberculosis (MTb) that are capable to significantly shorten the treatment duration, and are active against MDR-TB and latent infection.
The general concept of the present proposal is to target the MTb system(s) forming a core maintenance function of bacterial metabolism. In the majority of infected people, after entry in the organism, MTb becomes latent, encapsulated in macrophages surrounded by other immune cells. The bacilli can survive for years in such a state and reactivate to develop active TB once the immune system control weakens or fails. A number of promising targets are found in tubercle bacilli that are important for viability, yet mostly during the active growth phase, and not in maintenance functions during the latent state. Drugs targeting such proteins can only kill actively growing bacilli. That is why complete elimination of TB is only possible if compounds capable to kill MTb in the latent state will be developed.
Recent discovery of a compound inhibiting the proton pump of the MTb ATP synthase, and highly active against Mycobacteria strongly supports the above concept. ATP is the main energy currency, and it synthesis is vital for bacteria regardless of the life cycle stage.
NAD is another compound likely to be essential for the MTb at growth and latent phases. During active growth, NAD is required for the lipid biosynthesis, DNA repair, recombination, and replication, a variety of redox reactions. On the other hand, NAD is required for maintenance of the latent state of infection and for priming MTb for reactivation following latency. Like in the case of ATP synthase inhibition, compounds inhibiting the NAD synthesis machinery can be promising candidate antitubercular drugs irrespective of the growth phase of the bacterium
The aim of this Proposal is to identify small-molecule compounds with inhibitory activity against two essential enzymes of the NAD biosynthetic pathway, NaMN adenyltransferase, and NAD+ synthetase to validate these enzymes as suitable drug targets in Mtb. Genome-wide analyses have validated these enzymes as essential for bacterial survival. Recently, several compounds inhibiting bacterial NAD+ synthetase in vitro were shown to possess antibacterial activity against some Gram-positive bacteria.
The goal of the Project is to demonstrate that the interruption of the NAD biosynthesis leads to killing the MTb, thus paving the way to development of new antitubercular drug or at a minimum, provide small molecule tools to further elucidate the role of these enzymes during the various growth stages of Mtb. Once compounds blocking NAD+ biosynthesis and displaying the inhibitory activity against the MTb in vitro are identified, they will be tested in vivo using a rapid mouse model of TB infection.
This is a multidisciplinary project that involves microbiologists, organic and computation chemists, biochemists and molecular biologists