Cinnamide Derivatives of d -Mannose as Inhibitors of the Bacterial Virulence Factor LecB from Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa is an opportunistic Gram‐negative pathogen with high antibiotic resistance. Its lectin LecB was identified as a virulence factor and is relevant in bacterial adhesion and biofilm formation. Inhibition of LecB with carbohydrate‐based ligands results in a decrease in toxicity and biofilm formation. We recently discovered two classes of potent drug‐like glycomimetic inhibitors, that is, sulfonamides and cinnamides of d‐mannose. Here, we describe the chemical synthesis and biochemical evaluation of more than 20 derivatives with increased potency compared to the unsubstituted cinnamide. The structure–activity relationship (SAR) obtained and the extended biophysical characterization allowed the experimental determination of the binding mode of these cinnamides with LecB. The established surface binding mode now allows future rational structure‐based drug design. Importantly, all glycomimetics tested showed extended receptor residence times with half‐lives in the 5–20 min range, a prerequisite for therapeutic application. Thus, the glycomimetics described here provide an excellent basis for future development of anti‐infectives against this multidrug‐resistant pathogen.

Development of a competitive binding assay for the Burkholderia cenocepacia lectin BC2L-A and structure activity relationship of natural and synthetic inhibitors

“…sulfonamide substituents in position 6 were previously reported as potent inhibitors of LecB. 22,31 However, since these compounds lack a free hydroxy group in position 6, the observed lack of inhibition of BC2L-A (data not shown) was consistent with the observations for the relative behavior of e.g., compound 9 and 10. We were further interested in the importance of the ring hydroxy groups for binding, which are directly coordinating to the two Ca 2+ ions in BC2L-A or in the related P. aeruginosa LecB.…”

Contribution of Lewis blood groups molecules in biofilm formation of Pseudomonas aeruginosa isolated from atopic dermatitis patients.

“…What is peculiar in this investigation is that atopic dermatitis manifested increase isolation frequency of P. aeruginosa, a situation that might implicate this microorganism in the pathogenesis of this multifactorial-based disease [11]. P. aeruginosa have Lec(A) and Lec(B) (PA1L and PA11L) Lectins, mediating bacterial pathogenesis through biofilm formation [12][13][14][15]. The Ligand presumed to be Le(a) which is involved in biofilm formation as seen in this report could mediate colonization of the bacteria to skin and colon of atopic dermatitis [16].…”

Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections

“…For a future systemic application, Titz et al have developed small molecule LecB inhibitors derived from mannose and obtained potent monovalent inhibitors (compound 15 ) of LecB-mediated bacterial adhesion [ 47 ]. The sulfonamide 15 and cinnamide 16 were developed to take advantage of interactions with a nearby shallow pocket, and indeed these compounds showed superior thermodynamics and kinetics of binding to LecB compared to mannose, resulting in a prolonged receptor residence time of several minutes [ 48 ]. In a complementary approach, glycomimetic C -glycoside 17 was obtained, aiming at improved metabolic stability and selectivity [ 49 ].…”