In Vitro and In Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas

Ottavi S, Scarry SM, Mosior J, Ling Y, Roberts J, Singh A, Zhang D, Goullieux L, Roubert C, Bacqué E, Lagiakos HR, Vendome J, Moraca F, Li K, Perkowski AJ, Ramesh R, Bowler MM, Tracy W, Feher VA, Sacchettini JC, Gold BS, Nathan CF, and Aubé J.

Journal of Medicinal Chemistry, 2022

Scientists explore new therapeutic target for tuberculosis and assess potential cardiotoxicity using Axion’s Maestro MEA platform

Tuberculosis remains a leading cause of death worldwide, and new therapies with novel mechanisms of action are urgently needed to combat increasing drug resistance and shorten lengthy treatment regimens. Phosphopantetheinyl phosphoryl transferase (PptT) — an enzyme that plays a key role in the biosynthesis of cellular lipids and virulence in Mycobacterium tuberculosis — is a newly identified therapeutic target for the bacterial infection. In this study, scientists investigate the structure-activity relationship of a recently disclosed PptT inhibitor, amidinourea (AU) 8918, and test a series of analogues in vitro.

To explore potential cardiotoxic effects of AU 8918 in real time, the researchers used Axion’s noninvasive Maestro multielectrode array (MEA). The findings revealed that although many PptT-active analogues resulted in cardiotoxicity — displaying changes in cardiac beat rate, amplitude, and peak width, as well as inhibiting ion channels — others demonstrated potent on - target activity and limited cardiotoxic effects, suggesting that the cardiotoxicity is not an intrinsic feature of PptT inhibition. Overall, the results suggest that the inhibition of PptT is a promising target for the treatment of tuberculosis, but more research is needed.