Abstract
Peptide deformylase (PDF) is considered an excellent target to develop antibiotics. We have performed an extensive characterization of a new PDF from the pathogen Streptococcus agalactiae, showing properties similar to other known PDFs. S. agalactiae PDF could be used as PDF prototype as it allowed to get complete sets of 3-dimensional, biophysical and kinetic data with virtually any inhibitor compound. Structure-activity relationship analysis with this single reference system allowed us to reveal distinct binding modes for different PDF inhibitors and the key role of a hydrogen bond in potentiating the interaction between ligand and target. We propose this protein as an irreplaceable tool, allowing easy and relevant fine comparisons between series, to design, challenge and validate novel series of inhibitors. As proof-of-concept, we report here the design and synthesis of effective specific bacterial PDF inhibitors of an oxadiazole series with potent antimicrobial activity against a multidrug resistant clinical isolate.
Highlights
The reference compound for the rational design of new anti-PDF compounds because of its high potency attained through a two-step, time-dependent inhibition mechanism called slow tight-binding
These results revealed distinct binding modes for the different PDF inhibitors (PDFIs) and provide additional criteria defining the basic chemical structure that any PDF inhibitor should display in order to reach high efficiency
To get a relevant PDF originating from pathogenic bacteria, we chose the defB-encoded PDF2 from the Gram positive bacterium Streptococcus agalactiae (SaPDF), whose infections cause neonatal sepsis and meningitis in newborn infants[54]
Summary
The reference compound for the rational design of new anti-PDF compounds because of its high potency attained through a two-step, time-dependent inhibition mechanism called slow tight-binding In this context, actinonin (Inhibitor, I) initially and rapidly binds the enzyme (E) with a rather low inhibitory constant (KI). The synergic application of a variety of complementary biochemical approaches along with the X-ray crystallography data analysis allowed to: (i) measure dissociation and inhibition constants for each PDFI (ii) describe their binding site at atomic resolution and (iii) visualize a conformational change induced by one ligand Together, these results revealed distinct binding modes for the different PDFIs and provide additional criteria defining the basic chemical structure that any PDF inhibitor should display in order to reach high efficiency. We identified promising inhibitors derived from an oxadiazole core displaying higher activity against clinical resistant strains compared to the antibiotics currently in use
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