Bioinspired acetylenic molecules for antituberculosis drug development – Beam4TB

Tuberculosis (TB), caused by the Koch bacillus Mycobacterium tuberculosis (Mtb), is a millennial global health problem, still responsible today for 1.4 million deaths and approximately 10 million new cases each year. Facing the lack of efficacy of vaccination, the emergence of antibiotic-resistant strains of Mtb adds an alarming dimension to a situation aggravated by the COVID-19 pandemic. Such an antibioresistance calls for the discovery of novel chemical families of antibiotics, acting by new mechanisms and/or on new Mtb targets.
For this purpose, we focused on the family, still uncommon in the pharmacopoeia, of acetylenic lipids, and more precisely "lipidic alkynylcarbinols" (LACs), some bio-inspired representatives of which have proven to be anti-cancer agents of a new type. More recent results have thus shown that certain LACs also act in vitro as remarkable anti-tuberculosis agents, while presenting a structural analogy with natural LACs extracted from traditional anti-infectious medicinal plants (falcarinol and falcarindiol). We have thus identified two types of anti-Mtb LACs, as active as isoniazid (prescribed for a long time as a first-line anti-tuberculosis drug), and showing low cytotoxicity on human cells, including host macrophages of Mtb in infected persons. These two types of LACs have the particularity of being quickly accessible by chemical synthesis in 2 to 5 steps, but also readily versatile.
As an extension of the established chemo-biology results, the objectives of the project are (i) to evaluate the pharmacokinetic properties and toxicity of four pre-selected particular LACs, (ii) to determine their therapeutic efficacy in a mouse model of TB, (iii) to elucidate their mechanism of action (MOA) by identifying their target(s) in Mtb, and (iv) to optimize their chemical structure.
The ultimate objective will be to enable and guide the development of antimycobacterial drugs that would be both innovative in terms of MOA to feed the anti-TB arsenal against sensitive and antibio-resistant strains of Mtb, and accessible to developing countries where TB is endemic.