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Tubercular  Mycobacteria  and  Legionella pneumophila  are the causative agents of potentially fatal respiratory diseases due to their intrinsic pathogenesis but also due to the emergence of antibiotic resistance that limits treatment options. The aim of our study was to explore the antimicrobial activity of a small ligand-based chemical library of 1255 structurally diverse compounds. These compounds were screened in a combination of three assays, two monitoring the intracellular growth of the pathogenic bacteria,  Mycobacterium marinum  and  L. pneumophila , and one assessing virulence of  M. marinum . We set up these assays using two amoeba strains, the genetically tractable social amoeba  Dictyostelium discoideum  and the free-living amoeba  Acanthamoeba castellanii . In summary, 64 (5.1%) compounds showed anti-infective/anti-virulence activity in at least one of the three assays. The intracellular assays hit rate varied between 1.7% ( n  = 22) for  M. marinum  and 2.8% ( n  = 35) for  L. pneumophila  with seven compounds in common for both pathogens. In parallel, 1.2% ( n  = 15) of the tested compounds were able to restore  D. discoideum  growth in the presence of  M. marinum  spiked in a lawn of food bacteria. We also validated the generality of the hits identified in the  A. castellanii – M. marinum  anti-infective screen using the  D. discoideum – M. marinum  host–pathogen model. The characterization of anti-infective and antibacterial hits in the latter infection model revealed compounds able to reduce intracellular growth more than 50% at 30 μM. Moreover, the chemical space and physico-chemical properties of the anti- M. marinum  hits were compared to standard and candidate  Mycobacterium tuberculosis  (Mtb) drugs using ChemGPS-NP. A principle component analysis identified separate clusters for anti- M. marinum  and anti- L. pneumophila  hits unveiling the potentially new physico-chemical properties of these hits compared to standard and candidate  M. tuberculosis  drugs. Our studies underscore the relevance of using a combination of low-cost and low-complexity assays with full 3R compliance in concert with a rationalized focused library of compounds to identify new chemical scaffolds and to dissect some of their properties prior to taking further steps toward compound development.

frontiers in microbiology

Identification of Anti-Mycobacterium and Anti-Legionella Compounds With Potential Distinctive Structural Scaffolds From an HD-PBL Using Phenotypic Screens in Amoebae Host Models