Dataset Information

Overcoming antibiotic resistance in Pseudomonas aeruginosa biofilms using glycopeptide dendrimers.

ABSTRACT: Antibiotic resistance in the opportunistic pathogen Pseudomonas aeruginosa is partly caused by biofilms forming a physical barrier to antibiotic penetration. Here we focused on modifying tetravalent glycopeptide dendrimer ligands of P. aeruginosa lectins LecB or LecA to increase their biofilm inhibition activity. First heteroglycoclusters were investigated displaying one pair each of LecB specific fucosyl groups and LecA specific galactosyl groups and binding simultaneously to both lectins, one of which gave the first fully resolved crystal structure of a peptide dendrimer as LecB complex providing a structural model for dendrimer-lectin interactions (PDB ; 5D2A). Biofilm inhibition was increased by introducing additional cationic residues in these dendrimers but resulted in bactericidal effects similar to those of non-glycosylated polycationic antimicrobial peptide dendrimers. In a second approach dendrimers displaying four copies of the natural LecB ligand Lewisa were prepared leading to slightly stronger LecB binding and biofilm inhibition. Finally synergistic application of a LecB specific non-bactericidal antibiofilm dendrimer with the antibiotic tobramycin at sub-inhibitory concentrations of both compounds allowed effective biofilm inhibition and dispersal.

SUBMITTER: Michaud G

PROVIDER: S-EPMC5953009 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Overcoming antibiotic resistance in Pseudomonas aeruginosa biofilms using glycopeptide dendrimers.

Michaud Gaëlle G Visini Ricardo R Bergmann Myriam M Salerno Gianluca G Bosco Rosa R Gillon Emilie E Richichi Barbara B Nativi Cristina C Imberty Anne A Stocker Achim A Darbre Tamis T Reymond Jean-Louis JL

Chemical science 20151125 1

Antibiotic resistance in the opportunistic pathogen Pseudomonas aeruginosa is partly caused by biofilms forming a physical barrier to antibiotic penetration. Here we focused on modifying tetravalent glycopeptide dendrimer ligands of P. aeruginosa lectins LecB or LecA to increase their biofilm inhibition activity. First heteroglycoclusters were investigated displaying one pair each of LecB specific fucosyl groups and LecA specific galactosyl groups and binding simultaneously to both ...[more]

PMID: 29896342

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Project description:Clinicians prescribe hundreds of millions of ?-lactam antibiotics to treat the majority of patients presenting with bacterial infections. Patient outcomes are positive unless resistant bacteria, such as Pseudomonas aeruginosa (P. aeruginosa), are present. P. aeruginosa has both intrinsic and acquired antibiotic resistance, making clinical management of infection a real challenge, particularly when these bacteria are sequestered in biofilms. These problems would be alleviated if, upon the initial presentation of bacterial infection symptoms, clinicians were able to administer an antibiotic that kills both susceptible and otherwise resistant bacteria and eradicates biofilms. As the most common class of antibiotics, ?-lactams could be used in a new drug if the leading causes of ?-lactam antibiotic resistance, permeation barriers from lipopolysaccharide, efflux pumps, and ?-lactamase enzymes, were also defeated. Against P. aeruginosa and their biofilms, the potency of ?-lactam antibiotics is restored with 600 Da branched polyethylenimine (600 Da BPEI). Checkerboard assays using microtiter plates demonstrate the potentiation of piperacillin, cefepime, Meropenem, and erythromycin antibiotics. Growth curves demonstrate that only a combination of 600 Da BPEI and piperacillin produces growth inhibition against antibiotic resistant P. aeruginosa. Scanning electron microscopy (SEM) was used to confirm that the combination treatment leads to abnormal P. aeruginosa morphology. Data collected with isothermal titration calorimetry and fluorescence spectroscopy demonstrate a mechanism of action in which potentiation at low concentrations of 600 Da BPEI reduces diffusion barriers from lipopolysaccharides without disrupting the outer membrane itself. Coupled with the ability to overcome a reduction in antibiotic activity created by biofilm exopolymers, targeting anionic sites on lipopolysaccharides and biofilm exopolysaccharides with the same compound provides new opportunities to counter the rise of multidrug-resistant infections.

Dataset Information

Overcoming antibiotic resistance in Pseudomonas aeruginosa biofilms using glycopeptide dendrimers.

Publications

Overcoming antibiotic resistance in <i>Pseudomonas aeruginosa</i> biofilms using glycopeptide dendrimers.

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