[Show abstract][Hide abstract] ABSTRACT: Macrophage infectivity potentiators (Mips) are immunophilin proteins and essential virulence factors for a range of pathogenic
organisms. We applied a structural biology approach to characterize a Mip from Burkholderia pseudomallei (BpML1), the causative agent of melioidosis. Crystal structure and nuclear magnetic resonance analyses of BpML1 in complex
with known macrocyclics and other derivatives led to the identification of a key chemical scaffold. This scaffold possesses
inhibitory potency for BpML1 without the immunosuppressive components of related macrocyclic agents. Biophysical characterization
of a compound series with this scaffold allowed binding site specificity in solution and potency determinations for rank ordering
the set. The best compounds in this series possessed a low-micromolar affinity for BpML1, bound at the site of enzymatic activity,
and inhibited a panel of homologous Mip proteins from other pathogenic bacteria, without demonstrating toxicity in human macrophages.
Importantly, the in vitro activity of BpML1 was reduced by these compounds, leading to decreased macrophage infectivity and intracellular growth of
Burkholderia pseudomallei. These compounds offer the potential for activity against a new class of antimicrobial targets and present the utility of
a structure-based approach for novel antimicrobial drug discovery.
Full-text · Article · Mar 2014 · Antimicrobial Agents and Chemotherapy
[Show abstract][Hide abstract] ABSTRACT: The macrophage infectivity potentiator (MIP) protein is a major virulence factor of Legionella pneumophila, the causative agent of Legionnaires' disease. MIP belongs to the FK506-binding proteins (FKBP) and is necessary for optimal intracellular survival and lung tissue dissemination of L. pneumophila. We aimed to identify new small-molecule inhibitors of MIP by starting from known FKBP12 ligands. Computational analysis, synthesis, and biological testing of pipecolic acid derivatives revealed a promising scaffold for new MIP inhibitors.
No preview · Article · Dec 2010 · Journal of Medicinal Chemistry