title: 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.
authors.forename: Diana
authors.initials: D
authors.lastname: Cordero
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Fullenkamp
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Pelly
authors.forename: Katie M
authors.initials: KM
authors.lastname: Reed
authors.forename: Lindy M
authors.initials: LM
authors.lastname: Caffo
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Zahrt
authors.forename: Micaleah
authors.initials: M
authors.lastname: Newman
authors.forename: Sarah
authors.initials: S
authors.lastname: Komanapalli
authors.forename: Evan M
authors.initials: EM
authors.lastname: Niemeier
authors.forename: Derron L
authors.initials: DL
authors.lastname: Bishop
authors.forename: Heather A
authors.initials: HA
authors.lastname: Bruns
authors.forename: Mark K
authors.initials: MK
authors.lastname: Haynes
authors.forename: Larry A
authors.initials: LA
authors.lastname: Sklar
authors.forename: Robert E
authors.initials: RE
authors.lastname: Sammelson
authors.affiliation: Cooper Science Complex, CL 171C, 2111 Riverside Ave. Ball State University, Muncie, IN 47306, USA. samcdowell@bsu.edu.
authors.forename: Susan A
authors.initials: SA
authors.lastname: McDowell
mesh_terms: D001422:Bacterial Adhesion; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000382:microbiology; D006801:Humans; D065636:Myotonin-Protein Kinase / Q000037:antagonists & inhibitors; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects*
chemical_list: D054852:Small Molecule Libraries; C105518:CDC42BPA protein, human; D065636:Myotonin-Protein Kinase