D-Enantiomeric Peptides that Eradicate Wild-Type and Multidrug-Resistant Biofilms and Protect against Lethal Pseudomonas aeruginosa Infections

被引:251
作者
de la Fuente-Nunez, Cesar [1 ]
Reffuveille, Fany [1 ]
Mansour, Sarah C. [1 ]
Reckseidler-Zenteno, Shauna L. [2 ]
Hernandez, Diego [2 ]
Brackman, Gilles [3 ]
Coenye, Tom [3 ]
Hancock, Robert E. W. [1 ]
机构
[1] Univ British Columbia, Ctr Microbial Dis & Immun Res, Dept Microbiol & Immunol, Vancouver, BC V6T 1Z4, Canada
[2] Athabasca Univ, Fac Sci & Technol, Athabasca, AB T9S 3A3, Canada
[3] Univ Ghent, Lab Pharmaceut Microbiol, B-9000 Ghent, Belgium
来源
CHEMISTRY & BIOLOGY | 2015年 / 22卷 / 02期
关键词
ANTIMICROBIAL PEPTIDES; BACTERIAL BIOFILMS; BROAD-SPECTRUM; BAD BUGS; IN-VIVO; SUSCEPTIBILITY; (P)PPGPP; LL-37; MECHANISMS; EXPRESSION;
D O I
10.1016/j.chembiol.2015.01.002
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 wildtype 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.
引用
收藏
页码:196 / 205
页数:10
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