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D-enantiomeric peptides that eradicate wild-type and multidrug-resistant biofilms and protect against lethal Pseudomonas aeruginosa infections.

ABSTRACT: In many infections, bacteria form surface-associated communities known as biofilms that are substantially more resistant to antibiotics than their planktonic counterparts. Based on the design features of active antibiofilm peptides, we made a series of related 12-amino acid L-, D- and retro-inverso derivatives. Specific D-enantiomeric peptides were the most potent at inhibiting biofilm development and eradicating preformed biofilms of seven species of wild-type and multiply antibiotic-resistant Gram-negative pathogens. Moreover, these peptides showed strong synergy with conventional antibiotics, reducing the antibiotic concentrations required for complete biofilm inhibition by up to 64-fold. As shown previously for 1018, these D-amino acid peptides targeted the intracellular stringent response signal (p)ppGpp. The most potent peptides DJK-5 and DJK-6 protected invertebrates from lethal Pseudomonas aeruginosa infections and were considerably more active than a previously described L-amino acid peptide 1018. Thus, the protease-resistant peptides produced here were more effective both in vitro and in vivo.

SUBMITTER: de la Fuente-Nunez C

PROVIDER: S-EPMC4362967 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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D-enantiomeric peptides that eradicate wild-type and multidrug-resistant biofilms and protect against lethal Pseudomonas aeruginosa infections.

de la Fuente-Núñez César C Reffuveille Fany F Mansour Sarah C SC Reckseidler-Zenteno Shauna L SL Hernández Diego D Brackman Gilles G Coenye Tom T Hancock Robert E W RE

Chemistry & biology 20150201 2

In many infections, bacteria form surface-associated communities known as biofilms that are substantially more resistant to antibiotics than their planktonic counterparts. Based on the design features of active antibiofilm peptides, we made a series of related 12-amino acid L-, D- and retro-inverso derivatives. Specific D-enantiomeric peptides were the most potent at inhibiting biofilm development and eradicating preformed biofilms of seven species of wild-type and multiply antibiotic-resistant ...[more]

PMID: 25699603

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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

D-enantiomeric peptides that eradicate wild-type and multidrug-resistant biofilms and protect against lethal Pseudomonas aeruginosa infections.

Publications

D-enantiomeric peptides that eradicate wild-type and multidrug-resistant biofilms and protect against lethal Pseudomonas aeruginosa infections.

Similar Datasets

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