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Novel engineered peptides of a phage lysin as effective antimicrobials against multidrug-resistant Acinetobacter baumannii

Thandar, Mya; Lood, Rolf LU ; Winer, Benjamin Y.; Deutsch, Douglas R.; Euler, Chad W. and Fischetti, Vincent A. (2016) In Antimicrobial Agents and Chemotherapy 60(5). p.2971-2979
Abstract

Acinetobacter baumannii is a Gram-negative bacterial pathogen responsible for a range of nosocomial infections. The recent rise and spread of multidrug-resistant A. baumannii clones has fueled a search for alternative therapies, including bacteriophage endolysins with potent antibacterial activities. A common feature of these lysins is the presence of a highly positively charged C-terminal domain with a likely role in promoting outer membrane penetration. In the present study, we show that the C-terminal amino acids 108 to 138 of phage lysin PlyF307, named P307, alone were sufficient to kill A. baumannii (>3 logs). Furthermore, P307 could be engineered for improved activity, the most active derivative being P307SQ-8C... (More)

Acinetobacter baumannii is a Gram-negative bacterial pathogen responsible for a range of nosocomial infections. The recent rise and spread of multidrug-resistant A. baumannii clones has fueled a search for alternative therapies, including bacteriophage endolysins with potent antibacterial activities. A common feature of these lysins is the presence of a highly positively charged C-terminal domain with a likely role in promoting outer membrane penetration. In the present study, we show that the C-terminal amino acids 108 to 138 of phage lysin PlyF307, named P307, alone were sufficient to kill A. baumannii (>3 logs). Furthermore, P307 could be engineered for improved activity, the most active derivative being P307SQ-8C (>5-log kill). Both P307 and P307SQ-8C showed high in vitro activity against A. baumannii in biofilms. Moreover, P307SQ-8C exhibited MICs comparable to those of levofloxacin and ceftazidime and acted synergistically with polymyxin B. Although the peptides were shown to kill by disrupting the bacterial cytoplasmic membrane, they did not lyse human red blood cells or B cells; however, serum was found to be inhibitory to lytic activity. In a murine model of A. baumannii skin infection, P307SQ-8C reduced the bacterial burden by ∼2 logs in 2 h. This study demonstrates the prospect of using peptide derivatives from bacteriophage lysins to treat topical infections and remove biofilms caused by Gram-negative pathogens.

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author
publishing date
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Contribution to journal
publication status
published
subject
in
Antimicrobial Agents and Chemotherapy
volume
60
issue
5
pages
9 pages
publisher
American Society for Microbiology
external identifiers
  • scopus:84964910629
  • wos:000377045600008
ISSN
0066-4804
DOI
10.1128/AAC.02972-15
language
English
LU publication?
no
id
3542394c-d295-4e5a-9287-323a3b08b4ca
date added to LUP
2016-06-01 13:05:42
date last changed
2017-10-01 05:20:10
@article{3542394c-d295-4e5a-9287-323a3b08b4ca,
  abstract     = {<p>Acinetobacter baumannii is a Gram-negative bacterial pathogen responsible for a range of nosocomial infections. The recent rise and spread of multidrug-resistant A. baumannii clones has fueled a search for alternative therapies, including bacteriophage endolysins with potent antibacterial activities. A common feature of these lysins is the presence of a highly positively charged C-terminal domain with a likely role in promoting outer membrane penetration. In the present study, we show that the C-terminal amino acids 108 to 138 of phage lysin PlyF307, named P307, alone were sufficient to kill A. baumannii (&gt;3 logs). Furthermore, P307 could be engineered for improved activity, the most active derivative being P307<sub>SQ-8C</sub> (&gt;5-log kill). Both P307 and P307<sub>SQ-8C</sub> showed high in vitro activity against A. baumannii in biofilms. Moreover, P307<sub>SQ-8C</sub> exhibited MICs comparable to those of levofloxacin and ceftazidime and acted synergistically with polymyxin B. Although the peptides were shown to kill by disrupting the bacterial cytoplasmic membrane, they did not lyse human red blood cells or B cells; however, serum was found to be inhibitory to lytic activity. In a murine model of A. baumannii skin infection, P307<sub>SQ-8C</sub> reduced the bacterial burden by ∼2 logs in 2 h. This study demonstrates the prospect of using peptide derivatives from bacteriophage lysins to treat topical infections and remove biofilms caused by Gram-negative pathogens.</p>},
  author       = {Thandar, Mya and Lood, Rolf and Winer, Benjamin Y. and Deutsch, Douglas R. and Euler, Chad W. and Fischetti, Vincent A.},
  issn         = {0066-4804},
  language     = {eng},
  number       = {5},
  pages        = {2971--2979},
  publisher    = {American Society for Microbiology},
  series       = {Antimicrobial Agents and Chemotherapy},
  title        = {Novel engineered peptides of a phage lysin as effective antimicrobials against multidrug-resistant Acinetobacter baumannii},
  url          = {http://dx.doi.org/10.1128/AAC.02972-15},
  volume       = {60},
  year         = {2016},
}