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Abstract
Owing to their role in activating enzymes essential for bacterial viability and pathogenicity, phosphopantetheinyl transferases represent novel and attractive drug targets. In this work, we examined the inhibitory effect of the aminido-urea 8918 compound against the phosphopantetheinyl transferases PptAb from Mycobacterium abscessus and PcpS from Pseudomonas aeruginosa, two pathogenic bacteria associated with cystic fibrosis and bronchiectasis, respectively. Compound 8918 exhibits inhibitory activity against PptAb but displays no activity against PcpS in vitro, while no antimicrobial activity against Mycobacterium abscessus or Pseudomonas aeruginosa could be detected. X-ray crystallographic analysis of 8918 bound to PptAb-CoA alone and in complex with an acyl carrier protein domain in addition to the crystal structure of PcpS in complex with CoA revealed the structural basis for the inhibition mechanism of PptAb by 8918 and its ineffectiveness against PcpS. Finally, in crystallo screening of potent inhibitors from the National Cancer Institute library identified a hydroxypyrimidinethione derivative that binds PptAb. Both compounds could serve as scaffolds for the future development of phosphopantetheinyl transferases inhibitors.
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Details
1 IPBS, Université de Toulouse, CNRS, UPS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France (GRID:grid.461904.e) (ISNI:0000 0000 9679 268X); CBS, CNRS, INSERM, Université de Montpellier, Centre de Biochimie Structurale, Montpellier, France (GRID:grid.462825.f) (ISNI:0000 0004 0639 1954)
2 IPBS, Université de Toulouse, CNRS, UPS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France (GRID:grid.461904.e) (ISNI:0000 0000 9679 268X)
3 Université de Toulouse, CNRS, UPS, Laboratoire de Synthèse et Physico-Chimie de Molécules d’Intérêt Biologique, LSPCMIB, Toulouse, France (GRID:grid.15781.3a) (ISNI:0000 0001 0723 035X); Evotec (France), Toulouse, France (GRID:grid.15781.3a)
4 Université de Toulouse, CNRS, UPS, Laboratoire de Synthèse et Physico-Chimie de Molécules d’Intérêt Biologique, LSPCMIB, Toulouse, France (GRID:grid.15781.3a) (ISNI:0000 0001 0723 035X)
5 IPBS, Université de Toulouse, CNRS, UPS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France (GRID:grid.461904.e) (ISNI:0000 0000 9679 268X); University of Colorado School of Medicine, Department of Pharmacology, Aurora, USA (GRID:grid.430503.1) (ISNI:0000 0001 0703 675X)