Targeting host lipid homeostasis to augment anti-mycobacterial treatment
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), represents one of the most prevalent infectious diseases, and is responsible for the largest fraction of infection-related casualties (before HIV). The disease usually affects the lung, and is controlled using extended antibiotic therapy, consisting of a daily regimen with isoniazid, rifampicin, pyrazinamide and ethambutol for two months, followed by a daily regimen with isoniazid and rifampicin for another four months. The vast majority of individuals infected with drug susceptible Mtb can be effectively cured when medicines are provided and taken properly. However, inappropriate use of drugs, use of ineffective formulations, and/or premature treatment interruption can cause drug resistance. According to WHO estimates, 0.5 million people were infected with multidrug-resistant (MDR) TB in 2014, leading to 0.2 million deaths. One MDR-TB patient in ten was infected with an almost untreatable, extensively drug-resistant (XDR-TB) variant. Emergence of MDR-TB and XDR-TB urgently necessitates alternative approaches to improve TB treatment and control.
One option to improve TB treatment is to interfere with the formation of lipid-laden foamy macrophages in the host, as these cells are exploited by intracellular Mtb to access lipids as predominant carbon source. Investigating foamy macrophages within the lungs of TB patients and experimentally infected mice, researcher at the FZB found that Mtb promotes an accumulation of neutral lipids in the host via WNT6-induced expression of key lipid metabolic enzymes including acetyl-CoA carboxylase-2 (Acc2). Accordingly, host`s lipogenesis provides a novel target for a host-directed TB therapy. Inhibitors of lipogenesis in general and Acc2 in particular have been extensively studied in the past by others for the treatment of metabolic disorders, like obesity, NASH and hepatic steatosis etc., and could now be re-purposed for augmenting TB therapy.
The technology is available for in-licensing and/or co-development. With regard to the latter, FZB can contribute extensive scientific expertise in TB research (e.g. hosting the national and WHO supranational Mtb reference center), different established mouse models with human TB pathology, and an own clinic and Center for Clinical Studies, prepared to conduct (if applicable) first feasibility studies in TB patients, and possibly to participate in further clinical trials.
FZB scientists have successfully tested several commercially available Acc inhibitors in different in vitro models using human macrophages, and observed a significant, concentration-dependent and consistent inhibition of Mtb growth. Notably, the Acc2 inhibitors showed no direct affect against Mtb, and were no toxic towards human macrophages. The novel approach is currently being tested in vivo. Initial data indicate that inhibitors of human Acc2 are able to inhibit Mtb growth also in established animal models, and to significantly improve standard TB therapy.
A priority-establishing patent application has been filed in 2016, followed by a PCT application in 2017. Applications are pending in EU, JP, RU and US.
J Brandenburg et al. (2019) Mycobacterium tuberculosis exploits WNT6-induced Acetyl-CoA Carboxylase-2 driven perturbation of host lipid homeostasis to facilitate growth in macrophages. Manuscript submitted.
Reiling & Brandenburg (2018) ACC inhibitors for use in treating mycobacterial diseases. WO/2018/007430.