Delamanid in Tuberculosis Management: a Novel Agent Against Drug-Resistant TB

Abstract

Tuberculosis (TB), primarily caused by Mycobacterium tuberculosis (MTB), continues to pose a significant health challenge worldwide, especially in regions like South-East Asia and Africa. This slow-growing, aerobic bacillus has a unique lipid-rich cell wall that makes it tough and resistant to many drugs. When someone inhales MTB, it targets the lungs and gets taken up by macrophages, which then form granulomas to try to contain the infection. While these granulomas can keep the bacteria dormant, a weakened immune system can trigger a reactivation, leading to active and contagious TB. The rise of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB has made traditional treatments like isoniazid and rifampicin less effective, highlighting the urgent need for new therapies. One promising option is Delamanid, an oral nitro-dihydro-imidazole derivative sold under the name Deltyba, which shows potential against MDR-TB. It works by being activated through the MTB F420 coenzyme system, inhibiting the synthesis of methoxy- and keto-mycolic acids that are essential for the bacteria's cell wall, ultimately leading to their death. Additionally, Delamanid creates oxidative and nitrosative stress through reactive nitrogen species. Clinical trials have shown that combining delamanid with WHO-recommended background treatments can lead to better outcomes and lower mortality rates. However, there is a risk of spontaneous resistance due to mutations in genes related to its activation. While delamanid is generally effective against M. tuberculosis, M. kansasii, and M. bovis, it doesn’t show significant activity against other bacterial species. Some side effects, like QTc prolongation, are mainly linked to its metabolite DM-6705. As a new therapy targeting the cell wall, delamanid is a crucial weapon in the fight against MDR-TB, with the potential to reduce transmission, enhance survival rates, and bolster global TB control initiatives.