Structural-guided fragment-based drug discovery applied to antitoxin, MAB3862 opens a new possibility of exploring the Toxin and Antitoxin for antibiotics

Abstract

AbstractMycobacterium abscessus (Mab) is a rapidly growing multidrug-resistant species among nontuberculous mycobacteria (NTM). Pulmonary infections caused by M. abscessus are difficult to treat and often result in an accelerated condition and premature death of immunosuppressed patients such as those with cystic fibrosis, putting them at a greater risk of other infections and increasing the urgency of developing a novel class of antibiotics. Here, we explore the use of toxin and antitoxin (TA) as an interesting and promising new class of target in a fragment-based drug-discovery approach. A de novo structure of Mab3862, an antitoxin of type 2 TA class in M. abscessus was elucidated and followed by drug discovery work. Very small molecules (fragments) are used to bind the antitoxin and then elaborated into drug-sized molecule that potentially trigger conformational change to prevent formation of toxin-antitoxin complex. Biophysical screening methods and binding-mode guidance from in silico docking were conducted. Grouping of fragments based on the binding site, creating a pharmacophore model, can facilitate further studies for rational design of inhibitors. Although targeting the TA complex for developing antibiotics is relatively novel and challenging, this could possibly open the gate for exploring it as potential drug target. Targeting one of the TA pairs might not be completely bactericidal. However, using this approach strategically with other antibiotics for synergic effect might be effective for patients with a persistence phenotype requiring prolonged therapy.