A drug candidate against Mycobacterium abscessus and other cystic fibrosis pathogens
Non-tuberculous mycobacteria (NTM) infections are becoming a threat to the life of people with cystic fibrosis (CF) as well as a major public health menace. Mycobacterium abscessus (Mab) is the pathogen of greatest concern amongst NTMs worldwide. Mab is intrinsically resistant to most available drugs, which generally lack bactericidal activity. Therefore, there is an urgent need of novel efficacious drugs against Mab.
In this study, we screened more than 700 compounds synthesized by Dr. V. Makarov and identified only one, 11226084, with bactericidal activity against Mab (MIC=0.25 mg/ml). 11226084 is also active against other NTMs including multi-drug resistant clinical isolates and other CF pathogens, such as Staphylococcus aureus and Acinetobacter baumannii. The molecule is also active against Mab biofilm and suitable for combinatorial therapy since no antagonism was identified among a panel of drugs clinically used for NTM treatment. Furthermore, 11226084is active in Mab-infected mice by intranasal administration, similar to amikacin, the drug comparator and is not toxic to the mice with good bioavailability.
Transcriptomic analysis showed that treatment with a 11226084 derivative inhibits essential metabolic pathways, such as cell division, protein biosynthesis, ATP production and gene transcription. Further studies elucidating the mode of action suggest that 11226084 could affect Mab cell division through FtsZ inhibition. In support of this finding, 11226084Mab treated cells displayed an elongated phenotype as evident from scanning electron microscopy studies.
The following experiments are in progress:
Further pharmacokinetic, metabolism and toxicity studies;
In depth characterization of its mechanism of action by heterologous production of Mab FtsZ;
Determination of its activity against both Mab non-replicant cells and in macrophages model;
Study of its activity in combination with gene correctors against both planktonic cells and biofilm.
Evaluation of its activity in Mab-infected mice using different concentrations by intranasal
Our results indicate that 11226084 is a promising anti-Mab drug candidate.
This work has received support from the “Fondazione Italiana Ricerca Fibrosi Cistica (FFC#18/2021,