Affiliation:
1. Department of Medicine, Division of Infectious Diseases, St. John’s Cardiovascular Research Center, LAC-Harbor University of California at Los Angeles Medical Center, Torrance, California 90509,1 and
2. School of Medicine, University of California at Los Angeles, Los Angeles, California 900242
Abstract
ABSTRACT
Thrombin-induced platelet microbicidal protein-1 (tPMP-1) and human neutrophil defensin-1 (HNP-1) are small, cationic antimicrobial peptides. These peptides exert potent in vitro microbicidal activity against a broad spectrum of human pathogens, including
Staphylococcus aureus
. Evidence suggests that tPMP-1 and HNP-1 target and disrupt the bacterial membrane. However, it is not yet clear whether membrane disruption itself is sufficient to kill the bacterium or whether subsequent, presumably intracellular, events are also involved in killing. We investigated the staphylocidal activities of tPMP-1 and HNP-1 in the presence or absence of pretreatment with antibiotics that differ in their mechanisms of action. The staphylocidal effects of tPMP-1 and HNP-1 on control cells (no antibiotic pretreatment) were rapid and concentration dependent. Pretreatment of
S. aureus
with either penicillin or vancomycin (bacterial cell wall synthesis inhibitors) significantly enhanced the anti-
S. aureus
effects of tPMP-1 compared with the effects against the respective control cells over the entire tPMP-1 concentration range tested (
P
< 0.05). Similarly,
S. aureus
cells pretreated with these antibiotics were more susceptible to HNP-1 than control cells, although the difference in the effects against cells that received penicillin pretreatment did not reach statistical significance (
P
< 0.05 for cells that received vancomycin pretreatment versus effects against control cells). Studies with isogenic pairs of strains with normal or deficient autolytic enzyme activities demonstrated that enhancement of
S. aureus
killing by cationic peptides and cell wall-active agents could not be ascribed to a predominant role of autolytic enzyme activation. Pretreatment of
S. aureus
cells with tetracycline, a 30S ribosomal subunit inhibitor, significantly decreased the staphylocidal effect of tPMP-1 over a wide peptide concentration range (0.16 to 1.25 μg/ml) (
P
< 0.05). Furthermore, pretreatment with novobiocin (an inhibitor of bacterial DNA gyrase subunit B) and with azithromycin, quinupristin, or dalfopristin (50S ribosomal subunit protein synthesis inhibitors) essentially blocked the
S. aureus
killing resulting from exposure to tPMP-1 or HNP-1 at most concentrations compared with the effects against the respective control cells (
P
< 0.05 for a tPMP-1 concentration range of 0.31 to 1.25 μg/ml and for an HNP-1 concentration range of 6.25 to 50 μg/ml). These findings suggest that tPMP-1 and HNP-1 exert anti-
S. aureus
activities through mechanisms involving both the cell membrane and intracellular targets.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
95 articles.
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