Small Molecule Inhibitors Limit Endothelial Cell Invasion by Staphylococcus aureus.

Abstract:

:Staphylococcus aureus is a leading causative agent in sepsis, endocarditis, and pneumonia. An emerging concept is that prognosis worsens when the infecting S. aureus strain has the capacity to not only colonize tissue as an extracellular pathogen, but to invade host cells and establish intracellular bacterial populations. In previous work, we identified host CDC42 as a central regulator of endothelial cell invasion by S. aureus. In the current work, we report that ML 141, a first-in-class CDC42 inhibitor, decreases invasion and resultant pathogenesis in a dose-dependent and reversible manner. Inhibition was found to be due in part to decreased remodeling of actin that potentially drives endocytic uptake of bacteria/fibronectin/integrin complexes. ML 141 decreased binding to fibronectin at these complexes, thereby limiting a key pathogenic mechanism used by S. aureus to invade. Structural analogs of ML 141 were synthesized (designated as the RSM series) and a subset identified that inhibit invasion through non-cytotoxic and non-bactericidal mechanisms. Our results support the development of adjunctive therapeutics targeting host CDC42 for mitigating invasive infection at the level of the host.

journal_name

Curr Pharm Biotechnol

authors

Cordero D,Fullenkamp CR,Pelly RR,Reed KM,Caffo LM,Zahrt AN,Newman M,Komanapalli S,Niemeier EM,Bishop DL,Bruns HA,Haynes MK,Sklar LA,Sammelson RE,McDowell SA

doi

10.2174/1389201015666140909124310

subject

Has Abstract

pub_date

2014-01-01 00:00:00

pages

727-37

issue

8

eissn

1389-2010

issn

1873-4316

pii

CPB-EPUB-62227

journal_volume

15

pub_type

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