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Inhibition of intracellular macromolecular synthesis in Staphylococcus aureus by thrombin-induced platelet
Yan-Qiong Xiong1, Arnold S Bayer, Michael R Yeaman
1Department of Medicine, Division of Infectious Diseases, St. John's Cardiovascular Research Center, Harbor-UCLA Research and Education Institute, Torrance, CA 90502, USA. Xiong@HUMC.edu
Abstract:
Thrombin-induced platelet microbicidal proteins (tPMP-1 and tPMP-2) are believed to initiate their staphylocidal effects via cytoplasmic membrane perturbation. The aim of the present study was to investigate the role of subsequent inhibition of macromolecular synthesis in the staphylocidal mechanisms of tPMP-1 and tPMP-2 in an isogenic tPMP-susceptible and -resistant strain pair (ISP479C and ISP479R, respectively). In ISP479C, tPMP-1 and tPMP-2 (2 microg/mL) exerted significant bactericidal effects and significantly reduced DNA and RNA synthesis (P <.05 vs. control). In contrast, tPMP-1 and tPMP-2 exerted reduced staphylocidal effects and significantly reduced inhibition of DNA and RNA synthesis against ISP479R, as compared with ISP479C (P <.05). However, tPMP-1 and tPMP-2 (2 microg/mL) caused equivalent degrees of inhibition of protein synthesis in both ISP479C and ISP479R. Collectively, these observations are consistent with the hypothesis that inhibition of specific macromolecular synthesis pathways is integral to the overall staphylocidal mechanism(s) of tPMPs.
Insights
Thrombin-induced platelet microbicidal proteins (tPMPs) kill Staphylococcus by disrupting membranes and inhibiting DNA/RNA synthesis. Resistance to tPMPs involves reduced inhibition of these processes, except for protein synthesis.
Area of Science:
- Microbiology
- Biochemistry
- Molecular Biology
Background:
- Thrombin-induced platelet microbicidal proteins (tPMPs) are potent antimicrobial agents.
- tPMPs are hypothesized to exert staphylocidal effects through cytoplasmic membrane perturbation.
- The role of macromolecular synthesis inhibition in tPMP mechanisms requires further elucidation.
Purpose of the Study:
- To investigate the role of macromolecular synthesis inhibition in the staphylocidal mechanisms of tPMP-1 and tPMP-2.
- To compare the effects of tPMPs on isogenic tPMP-susceptible (ISP479C) and -resistant (ISP479R) Staphylococcus strains.
- To determine if inhibition of DNA, RNA, or protein synthesis is integral to tPMP activity.
Main Methods:
- Utilized an isogenic pair of tPMP-susceptible (ISP479C) and -resistant (ISP479R) Staphylococcus strains.
- Administered tPMP-1 and tPMP-2 at 2 microg/mL to bacterial cultures.
- Quantified bactericidal effects and measured the inhibition of DNA, RNA, and protein synthesis.
Main Results:
- tPMP-1 and tPMP-2 demonstrated significant bactericidal effects and reduced DNA/RNA synthesis in the susceptible strain (ISP479C).
- In the resistant strain (ISP479R), tPMPs showed reduced staphylocidal activity and less inhibition of DNA/RNA synthesis compared to ISP479C.
- Inhibition of protein synthesis by tPMPs was equivalent in both susceptible and resistant strains.
Conclusions:
- The findings support the hypothesis that inhibition of specific macromolecular synthesis pathways is crucial for the staphylocidal action of tPMPs.
- Differential inhibition of DNA and RNA synthesis correlates with tPMP susceptibility and resistance.
- Protein synthesis inhibition is not the primary mechanism differentiating tPMP susceptibility.