Targeting energy of life for the development of drug combination to eradicate antibiotic-tolerant Mycobacterium abscessus, a clinical nightmare

The incidence and prevalence of non-tuberculous mycobacterial (NTM) infections have been increasing worldwide. Among rapidly growing NTM, Mycobacterium abscessus (Mab) is the most common pathogenic one in Singapore and the most drug resistant opportunistic one. Mab can cause pulmonary diseases, cutaneous- and catheter-related infections. The process of oxidative phosphorylation (OXPHOS) is the major process for the pathogen to synthesis the currency of life, ATP, making the pathogen vulnerable to potential drugs targeting this pathway. The enzyme complexes cyt-bc1-aa3 oxidase and F1FO-ATP synthase of Mab’s OXPHOS pathway are essential for growth. Our team has deciphered that a) Mab’s F-ATP synthase prevents ATP-waste by latency of ATP hydrolysis, and identified the regulative and Mab specific elements, providing novel compound targets. b) Described the essential role of the mycobacterial subunit δ in ATP synthesis, leading to the inhibitor DeMF1. c) Designed the anti-Mab compounds GaMF1 and (±)-C-118-F1. d) Determined the atomic solution structure of Mab F-ATP synthase subunit ε and the cryo-EM structure of the mycobacterial F1-ATPase, shining light on mechanistic features and Mab specific epitopes for novel compounds to bind. e) Deciphered critical amino acids of Mab’s cyt-bc1-aa3 oxidase for enzyme inhibition. The proposal describes a research program that will combine understanding and translation of OXPHOS operation of the pathogen Mab by forming a network of experts, whose overall goals are: a) To archive structural, enzymatic and mechanistic insights of the Mab’s cyt-bc1-aa3 and F-ATP synthase for novel target and hit identification. b) To design hit molecules of our unravelled DeMF1, GaMF1 and (±)-C-118-F1 F-ATP synthase inhibitors for the development of advanced lead molecules. c) To archive synergistic efficacy of multi-drug combination for drug resistant Mab, including the novel developed Mab F-ATP synthase and/or cyt-bc1-aa3 leads. d) To develop a preclinical development candidate. e) To establish an international clinical Mab network.