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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.

A woman, aged 52 years, experienced severe headache, confusion, nausea, dizziness, and diplopia for three days. Magnetic resonance imaging of the brain showed multiple acute and subacute infarcts suggestive of embolic events. Dermatological examination was notable for splinter hemorrhages and macular patches on the fingernails and feet, respectively. Further diagnostic imaging of the chest and abdomen revealed pulmonary emboli and an ovarian mass with omental deposits and splenic infarcts. Fine-needle aspiration cytology and surgery confirmed a diagnosis of high-grade serous adenocarcinoma of the ovary with clear cell features. Extensive evaluation for malignancy should be considered on a case-by-case basis for patients with thromboembolic disease and an initial negative diagnostic evaluation for stroke. Consideration of patent foramen ovale closure is reasonable in patients with malignancy who are at risk for recurrent strokes.

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