Mycobacterium tuberculosis is a successful pathogen, and it can survive in infected macrophages in dormant phase for years and decades. The
therapy of
tuberculosis takes at least six months, and the slow-growing bacterium is resistant to many
antibiotics. The development of novel antimicrobials to counter the emergence of bacteria resistant to current
therapies is urgently needed. In silico docking methods and structure-based drug design are useful bioinformatics tools for identifying new agents. A docking experiment to M.
tuberculosis dUTPase enzyme, which plays a key role in the bacterial metabolism, has resulted in 10 new
antitubercular drug candidates. The uptake of antituberculars by infected macrophages is limited by extracellular diffusion. The optimization of the cellular uptake by drug delivery systems can decrease the used dosages and the length of the
therapy, and it can also enhance the bioavailability of the drug molecule. In this study, improved in vitro efficacy was achieved by attaching the TB5
antitubercular drug candidate to
peptide carriers. As drug delivery components, (i) an antimicrobial granulysin
peptide and (ii) a receptor specific
tuftsin peptide were used. An efficient synthetic approach was developed to conjugate the in silico identified TB5
coumarone derivative to the carrier
peptides. The compounds were effective on M.
tuberculosis H37Rv culture in vitro; the chemical linkage did not affect the antimycobacterial activity. Here, we show that the OT20
tuftsin and GranF2 granulysin
peptide conjugates have dramatically enhanced uptake into human MonoMac6 cells. The TB5-OT20
tuftsin conjugate exhibited significant antimycobacterial activity on M.
tuberculosis H37Rv infected MonoMac6 cells and inhibited intracellular bacteria.