FFC#14/2020

New weapons against Mycobacterium abscessus and other nontuberculous mycobacteria

FFC#14/2020

New weapons against Mycobacterium abscessus and other nontuberculous mycobacteria

PRINCIPAL INVESTIGATOR

Maria Rosalia Pasca (Università degli Studi di Pavia, Dip. di Biologia e Biotecnologia Lazzaro Spallanzani)

Partner

Vladim Makarov (Federal Research Center, Moscow); Santiago Ramon-Garcia (University of Zaragoza); Enrico Tortoli (Div. di Immunologia, Trapianti e Malattie Infettive – HSR, Milano)

RESEARCHERS

12

CATEGORY

AREA 3 Bronchopulmonary infection

DURATION

1 year

GOAL

€ 57.000 €

RESULTS

The emergence of Mycobacterium abscessus as cystic fibrosis (CF) pathogen is a health threat worldwide because it is intrinsically resistant to several classes of antibiotics. For this reason, the researchers are looking for new drugs active against this worrisome CF pathogen following two routes: drug repurposing strategy and search for new molecules. By drug repurposing strategy, which is a useful procedure to reduce time and cost of disclosing novel drug candidates, the researchers found two compounds (mefloquine and a benzimidazole derivative) active against M. abscessus, other non-tuberculous mycobacteria (NTM), including multidrug-resistant (MDR) clinical isolates. The research team showed that both compounds interfere with mycolic acids biosynthesis, by inhibiting MmpL3 activity. They also found that one out of them, mefloquine, a well-known antimalarial, is suitable for combinational therapy. Following the second strategy, out of more than 700 tested compounds, one with a bactericidal activity against M. abscessus was identified. the researchers demonstrated that it is transformed in a metabolite, named with the code 11226084 which is active against M. abscessus, and other NTM and MDR clinical isolates. The preclinical evaluation of 11226084 is in progress. The researchers showed that it is bactericidal and is active against M. abscessus biofilm. It was evaluated that it is also active in M. abscessus infected mice by intranasal administration. Taking advantage of these achieved results further studies are needed to understand whether 11226084 is a promising drug candidate to be further investigated for M. abscessus therapy.

OTHER RESULTS

FFC#2/2022

Characterization of CFTR modulators mechanism of action via Photo-Affinity Labeling (PAL) approach

FFC#6/2022

Search for drug combinations killing Mycobacterium abscessus in cystic fibrosis

FFC#1/2021

Multiomics exploration of the CF primary bronchial epithelium lipidome and its role on CFTR rescue