Glycomimetic, Orally Bioavailable LecB Inhibitors Block Biofilm Formation of Pseudomonas aeruginosa

Abstract

The opportunistic Gram-negative bacterium Pseudomonas aeruginosa is a leading pathogen for infections of immuno-compromised patients and those suffering from cystic fibrosis. Its ability to switch from planktonic life to aggregates, forming the so-called biofilms, is a front-line mechanism of antimicrobial resistance. The bacterial carbohydrate-binding protein LecB is an integral component and necessary for biofilm formation. Here, we report a new class of drug-like low molecular weight inhibitors of the lectin LecB with nanomolar affinities and excellent receptor binding kinetics and thermodynamics. This class of glycomimetic inhibitors efficiently blocked biofilm formation of P. aeruginosa in vitro while the natural monovalent carbohydrate ligands failed. Furthermore, excellent selectivity and pharmacokinetic properties were achieved. Notably, two compounds showed good oral bioavailability, and high compound concentrations in plasma and urine were achieved in vivo.

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

“…Biofilm dispersal can be achieved by extracellular enzymes that are able to degrade EPS components.I nt his regard, various proteases,deoxyribonucleases,and glycoside hydrolases were shown to degrade the biofilm matrix. [246] Halogenated phenazine (HP) analogue 14, inspired by marine antibiotic 2-bromo-1-hydroxyphenezine, is able to efficiently eradicate biofilms formed by MRSA, methicillinresistant S. epiderimdis (MRSE), and VRE with minimum biofilm eradication concentrations (MBECs) of 12.5 mm, 1.56 mm,a nd 0.20 mm,r espectively.T his excellent potencyi s promising for future development. This compound is not only environmentally stable and exhibits activity against biofilm formation, but also causes dispersion of established biofilms, thus suggesting ah uge potential for further development of enzyme mimetics.…”

“…Moreover,g lycomimetic 7b exhibited good metabolic stability in ADME (absorption, distribution, metabolism, and excretion) experiments as well as oral bioavailability during in vivo studies.T he evaluation of this compound in animal models of infection will be needed to show its efficacy. [246] Halogenated phenazine (HP) analogue 14, inspired by marine antibiotic 2-bromo-1-hydroxyphenezine, is able to efficiently eradicate biofilms formed by MRSA, methicillinresistant S. epiderimdis (MRSE), and VRE with minimum biofilm eradication concentrations (MBECs) of 12.5 mm, 1.56 mm,a nd 0.20 mm,r espectively.T his excellent potencyi s promising for future development. Moreover,i ta lso kills persister cells effectively without showing toxicity to mammalian cells.…”

Pseudomonas aeruginosalectin LecB impairs keratinocyte fitness by abrogating growth factor signalling

“…Wound infections represent a socio-economic burden for the healthcare system and, given that P. aeruginosa is very hard to eliminate with the available antibiotics, there is urgent need for the development of alternative therapeutic strategies [54,55]. Taken together, our findings shed new light on the P. aeruginosa lectin LecB, showing that it is capable of inducing a succession of cellular events, despite being devoid of catalytic activity and by virtue of its sole capability to bind to sugar moieties on the plasma membrane, and can set the basis for a better understanding of P. aeruginosa wound infections.…”

Induction of Rare Conformation of Oligosaccharide by Binding to Calcium-dependent Bacterial Lectin: X-ray Crystallography and Modelling Study

“…Characterising the interaction of bacterial lectins with their natural ligands is of interest for the development of anti-infective compounds that are able to inhibit the adhesion of bacteria or the formation of biofilm [15]. For example, the structure of LecB complexed with Le a was used for the design of fucose derived glycomimetics with aromatic aglycone mimicking the GlcNAc ring [16] and mannose/fucose derived glycomimetics carrying sulphonamide substituents [17,18].…”