title: Microbicidal effects of α- and θ-defensins against antibiotic-resistant Staphylococcus aureus and Pseudomonas aeruginosa.
abstract: Antibiotic-resistant bacterial pathogens threaten public health. Because many antibiotics target specific bacterial enzymes or reactions, corresponding genes may mutate under selection and lead to antibiotic resistance. Accordingly, antimicrobials that selectively target overall microbial cell integrity may offer alternative approaches to therapeutic design. Naturally occurring mammalian α- and θ-defensins are potent, non-toxic microbicides that may be useful for treating infections by antibiotic-resistant pathogens because certain defensin peptides disrupt bacterial, but not mammalian, cell membranes. To test this concept, clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA), including vancomycin heteroresistant strains, and ciprofloxacin-resistant Pseudomonas aeruginosa (Cip(R)-PA) were tested for sensitivity to α-defensins Crp-4, RMAD-4 and HNPs 1-3, and to RTD-1, macaque θ-defensin-1. In vitro, 3 μM Crp-4, RMAD-4 and RTD-1 reduced MRSA cell survival by 99%, regardless of vancomycin susceptibility. For PA clinical isolates that differ in fluoroquinolone resistance and virulence phenotype, peptide efficacy was independent of strain ciprofloxacin resistance, site of isolation or virulence factor expression. Thus, Crp-4, RMAD-4 and RTD-1 are effective in vitro antimicrobials against clinical isolates of MRSA and Cip(R)-PA, perhaps providing templates for development of α- and θ-defensin-based microbicides against antibiotic resistant or virulent infectious agents.
authors.affiliation: Department of Pathology and Laboratory Medicine, USC Norris Cancer Center, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Tai
authors.affiliation: Department of Pathology and Laboratory Medicine, USC Norris Cancer Center, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Karishma
authors.initials: K
authors.lastname: Kamdar
authors.affiliation: Titus Family Department of Clinical Pharmacy and Pharmaceutical Economics and Policy, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Yamaki
authors.affiliation: Department of Pathology and Laboratory Medicine, USC Norris Cancer Center, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Valerie V
authors.initials: VV
authors.lastname: Le
authors.affiliation: Department of Pathology and Laboratory Medicine, USC Norris Cancer Center, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Dat
authors.initials: D
authors.lastname: Tran
authors.affiliation: Department of Pathology and Laboratory Medicine, USC Norris Cancer Center, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Patti
authors.initials: P
authors.lastname: Tran
authors.affiliation: Department of Pathology and Laboratory Medicine, USC Norris Cancer Center, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Selsted
authors.affiliation: Department of Pathology and Laboratory Medicine, USC Norris Cancer Center, Keck School of Medicine, Los Angeles, CA, USA aouellet@usc.edu.
authors.forename: André J
authors.initials: AJ
authors.lastname: Ouellette
authors.affiliation: Titus Family Department of Clinical Pharmacy and Pharmaceutical Economics and Policy, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Wong-Beringer
mesh_terms: D000595:Amino Acid Sequence; D016470:Bacteremia / Q000382:microbiology; D001424:Bacterial Infections / Q000382:microbiology; D002939:Ciprofloxacin / Q000494:pharmacology; D023082:Defensins / Q000235:genetics / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D020713:Vancomycin Resistance; D023084:alpha-Defensins / Q000235:genetics / Q000494:pharmacology*
chemical_list: D023082:Defensins; D023084:alpha-Defensins; C450142:theta-defensin; D002939:Ciprofloxacin
keywords: Antimicrobial peptides; ExoS; ExoU; bacteremia; clinical isolates; peptide therapeutics