title: Novel Engineered Peptides of a Phage Lysin as Effective Antimicrobials against Multidrug-Resistant Acinetobacter baumannii.
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 (>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.
authors: Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA.
authors: Mya
authors: M
authors: Thandar
authors: Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA.
authors: Rolf
authors: R
authors: Lood
authors: Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA.
authors: Benjamin Y
authors: BY
authors: Winer
authors: Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA.
authors: Douglas R
authors: DR
authors: Deutsch
authors: Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA.
authors: Chad W
authors: CW
authors: Euler
authors: Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA vaf@rockefeller.edu.
authors: Vincent A
authors: VA
authors: Fischetti
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000472:pathogenicity; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects; D002442:Ceftazidime / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D005260:Female; D064704:Levofloxacin / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000494:pharmacology; D011112:Polymyxin B / Q000494:pharmacology; D017433:Protein Structure, Secondary
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D010455:Peptides; D064704:Levofloxacin; D002442:Ceftazidime; D011112:Polymyxin B