Affiliation:
1. Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA
Abstract
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 P307
SQ-8C
(>5-log kill). Both P307 and P307
SQ-8C
showed high
in vitro
activity against
A. baumannii
in biofilms. Moreover, P307
SQ-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, P307
SQ-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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
108 articles.
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