Discovery of N,N'-diarylurea molecules with activity against multidrug-resistant Staphylococcus aureus.

The emergence and global spread of methicillin-resistant Staphylococcus aureus (MRSA) pose a serious threat to public health, underscoring the urgent need for novel antibacterial interventions. Here, we screened 18 newly synthesized N,N'-diarylurea derivatives to identify compounds with activity against MRSA. Our investigations led to the discovery of a small molecule, SCB-24, which exhibited promising antimicrobial activity against MRSA USA300. Notably, SCB-24 demonstrated high activity even in the presence of 10% fetal bovine serum and showed excellent selectivity for bacterial over mammalian cells. SCB-24 also showed potent activity against various MRSA strains, including those resistant to second- and third-line antibiotics. Importantly, the efficacy of SCB-24 was inferior to that of vancomycin in MRSA-infected Galleria mellonella larvae. Overall, our findings suggest that SCB-24 has great potential as a new therapeutic for multidrug-resistant S. aureus infections.

Rapid Bactericidal Activity of SC5005 Combined with Docosahexaenoic Acid against Multidrug-Resistant Staphylococcus aureus Persisters and Biofilms.

Staphylococcus aureus can form persister cells and biofilms, making the treatment difficult and often leading to recurrent infections. In an effort to discover new anti-staphylococcal agents, we observed that oleic acid enhances the activity of a new antibacterial agent, SC5005, against S. aureus and MRSA strains. Subsequent studies showed that saturated or trans-form unsaturated fatty acids did not potentiate SC5005's antibacterial activity. SC5005 only exhibits synergistic bactericidal activity with cis-form unsaturated fatty acids with 16 to 22 carbon atoms. In particular, docosahexaenoic acid (DHA) could reduce the MIC of SC5005 to the subng/mL range against different MRSA strains, including those resistant to second- and third-line antibiotics. However, we did not detect any significant shift in SC5005's cytotoxicity toward four different mammalian cell lines, suggesting that the synergy of DHA and SC5005 is highly selective. Most importantly, this combination demonstrated fast-killing activity, completely eradicating MRSA USA300 planktonic and persister cells within 10 and 30 min, respectively, and removing nearly 98% of MRSA biofilms within 1 min. Together, our findings suggest that the combination of SC5005 and DHA has great potential as a new therapeutic for the treatment of infections caused by multidrug-resistant (MDR) S. aureus biofilms.

Vaccinia virus protein F1L is a caspase-9 inhibitor.

Apoptosis plays important roles in host defense, including the elimination of virus-infected cells. The executioners of apoptosis are caspase family proteases. We report that vaccinia virus-encoded F1L protein, previously recognized as anti-apoptotic viral Bcl-2 family protein, is a caspase-9 inhibitor. F1L binds to and specifically inhibits caspase-9, the apical protease in the mitochondrial cell death pathway while failing to inhibit other caspases. In cells, F1L inhibits apoptosis and proteolytic processing of caspases induced by overexpression of caspase-9 but not caspase-8. An N-terminal region of F1L preceding the Bcl-2-like fold accounts for caspase-9 inhibition and significantly contributes to the anti-apoptotic activity of F1L. Viral F1L thus provides the first example of caspase inhibition by a Bcl-2 family member; it functions both as a suppressor of proapoptotic Bcl-2 family proteins and as an inhibitor of caspase-9, thereby neutralizing two sequential steps in the mitochondrial cell death pathway.