A new weapon against Mycobacterium abscessus

Ramón García, Santiago
45th European Cystic Fibrosis Conference
Participation type: 
Comunicación oral
Other authors: 
Giulia Degiacomi (presenter), Laurent R. Chiarelli, Lara Muñoz-Muñoz, Deborah Recchia, Giovanni Stelitano, Olga Riabova, Nicola I. Lorè, Natalia Monakhova, Fabio Saliu, Marco Rossi, José Maria Ezquerra Aznárez, Enrico Tortoli, Santiago Ramon-Garcia, Daniela Cirillo, Vadim Makarov, Maria Rosalia Pasca
Rotterdam, the Netherlands 8 - 11 June 2022

Non-tuberculous mycobacteria (NTM) infections are increasing, becoming a major public health menace, and threatening the life of cystic fibrosis (CF) individuals. Mycobacterium abscessus (Mab) is known as the most widespread and worrying pathogen amongst NTM. Mab requires a drug regimen that can last up to 2 years, with only about 30% of success. The recommended regimens generally lack efficacy and bactericidal activity. In fact, Mab is intrinsically resistant to many drugs, due to its physiology and acquisition of new mechanisms of drug resistance.
A new class of compounds, the hydropyridine class, endowed with anti-Mab activity emerged from a screening of more than 700 chemically synthesized compounds. Several derivatives of the hit compound were tested, and 11226084 was the most active (MIC=0.25 g/ml), showing activity against other mycobacterial species including NTM multidrug resistant isolates.
Interestingly, 11226084 is the active metabolite of the hit compound. It displays a bactericidal activity, as demonstrated by Time Killing Assay (TKA), and it is active against biofilm using both Calgary Biofilm Device and Confocal Laser Scanning Microscopy methods. Moreover, 11226084 is suitable for combinatorial therapy since no antagonism was identified by High-Throughput Synergy Screens, TKA and Checkerboard Assays.
Finally, the preliminary evaluation of in vivo activity showed that intranasally 11226084 administration is well tolerated and reduced the bacterial load in Mab infected mice.
The following studies are in progress: mechanism of action by target fishing; activity against non-replicant Mab cells; toxicity; synthesis of new derivatives; evaluation of its in vitro activity in combination with gene correctors; activity in mice infected with CF Mab clinical isolates; in vivo pharmacokinetics.
Concluding, 11226084 has the potential to become the next drug candidate in the anti-Mab drug pipeline.