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.
Keywords: CDC42, fibronectin, ML 141, MRSA, MSSA, pyrazolines, sepsis.
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