TY - JOUR
T1 - D-Enantiomeric Peptides that Eradicate Wild-Type and Multidrug-Resistant Biofilms and Protect against Lethal Pseudomonas aeruginosa Infections
AU - De La Fuente-Núñez, César
AU - Reffuveille, Fany
AU - Mansour, Sarah C.
AU - Reckseidler-Zenteno, Shauna L.
AU - Hernández, Diego
AU - Brackman, Gilles
AU - Coenye, Tom
AU - Hancock, Robert E.W.
N1 - Funding Information:
We thank Carmen Gibbs Allen and Neel Doshi for their expertise using the BioFlux device. We would also like to acknowledge George A. Mackie for his expertise and technical advice with the TLC work. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the NIH under Award Number R21AI098701, by a grant from the Canadian Institutes for Health Research MOP-74493 by the Fund for Scientific Research - Flanders (FWO-Vlaanderen), by the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen, SBO programme) and the Interuniversity Attraction Poles Programme initiated by the Belgian Science Policy Office. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. R.E.W.H. holds a Canada Research Chair in Health and Genomics. C.d.l.F.-N. received a scholarship from the Fundación “la Caixa” and Fundación Canadá (Spain). In addition, C.d.l.F.-N. and R.E.W.H. are coinventors of a provisional patent application on the use of cationic antibiofilm and innate defense regulator (IDR) peptides (US Patent Application No. 61/870,655).
Publisher Copyright:
© 2015 Elsevier Ltd.
PY - 2015/2/19
Y1 - 2015/2/19
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84923122512&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2015.01.002
DO - 10.1016/j.chembiol.2015.01.002
M3 - Journal Article
C2 - 25699603
AN - SCOPUS:84923122512
SN - 1074-5521
VL - 22
SP - 196
EP - 205
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 2
ER -