LALISTAT: TREATING MYCOBACTERIAL DISEASES
Tuberculosis, which is caused by mycobacteria, is the leading infectious disease thread worldwide, claiming 1.5 Million lives per year. Currentlytuberculosisis treatedbya combination therapy with the fou rantibiotics rifampicin, isoniazid, pyrazinamide, and ethambutol for two months, following a com- bination treatment with rifampicin and isoniazid for the last four months. However, the occurrence of multiresistant strains hinders an efficient treatment. Therefore, there is an urgent need for novel treatment options. One of the most important reasons for the development of resistances to antibiotics in mycobacteria is their ability of reprogramming host macrophages, the formation of granulomas and the state of dormancy.
Here the inventors could introduce a novel approach for inhibiting mycobacteria growth by the Lipase inhibitor Lalistat. Lalistat is a specific inhibitor of the lysosomal acid lipase, and can in contrast to the common inhibitor of lipases Orlistat specifically abrogate the intracellular growth of mycobacterium tuberculosis.
Figure: Lalistat inhibits M. tuberculosis growth. (A) Colony forming units (cfu) of M. tuberculosis H37Rv recovered from human macrophages in presence and absence of inhibitors. (B) Inhibition of GFP-expressing M. tuberculosis H37Rv with rifampicin (left) and lalistat (right). All experiments were performed together with the same DMSO cont- rol (identical in both graphs).
In recent years the occurrence of multidrug resistant tuberculosis strains drastically increased due to inappropriate use of antimycobacterial drugs, use of ineffective formulations or premature treatment interruption. Patients with multidrugresistantstrainshave a higher mortality rate and there is a public risk of spread of multidrug resistant strains if there is noadequatetreatment. Here, a novel promising treatment option for TB by the lysosomal acid lipase Lalistat is offered. The use of Lalistat in combina- tion with known antimycobacterial agents may offer an urgently needed opportunity to improve and shorten TB therapy.
Proof of concept in vitro