The COVID-19 pandemic demonstrated the public health benefits of reliable and accessible point-of-care (POC) diagnostic tests for viral infections. Despite the rapid development of gold-standard reverse transcription polymerase chain reaction...
Methicillin-resistant Staphylococcus aureus (MRSA) is a global healthcare concern. Such resistance has historically been attributed to the acquisition of mecA (or mecC), which encodes an alternative penicillin binding protein, PBP2a, with low β-lactam affinity. However, recent studies have indicated that penicillin binding protein 4 (PBP4) is also a critical determinant of S. aureus methicillin resistance, particularly among community-acquired MRSA strains. Thus, PBP4 has been considered an intriguing therapeutic target as corresponding inhibitors may restore MRSA β-lactam susceptibility. In addition to its role in antibiotic resistance, PBP4 has also recently been shown to be required for S. aureus cortical bone osteocyte lacuno-canalicular network (OLCN) invasion and colonization, providing the organism with a niche for re-occurring bone infection. From these perspectives, the development of PBP4 inhibitors may have tremendous impact as agents that both reverse methicillin resistance and inhibit the organism’s ability to cause chronic osteomyelitis. Accordingly, using a whole-cell high-throughput screen of a 30,000-member small molecule chemical library and secondary assays we identified putative S. aureus PBP4 inhibitors. Quantitative reverse transcriptase mediated PCR and PBP4 binding assays revealed that hits could be further distinguished as compounds that reduce PBP4 expression versus compounds that are likely to affect the protein’s function. We also showed that 6.25 µM (2.5 µg/mL) of the lead candidate, 9314848, reverses the organism’s PBP4-dependent MRSA phenotype and inhibits its ability to traverse Microfluidic-Silicon Membrane-Canalicular Arrays (µSiM-CA) that model the OLCN orifice. Collectively, these molecules may represent promising potential as PBP4-inhibitors that can be further developed as adjuvants for the treatment of MRSA infections and/or osteomyelitis prophylactics.
This work explores how to form and tailor the alloy composition of Fe/FexNi1-x core/alloy nanoparticles by annealing a pre-formed particle at elevated temperatures between 180 – 325 oC. This annealing allowed for a systematic FeNi alloying at a nanoparticle whose compositions and structure began as a alpha-Fe rich core, and a thin gamma-Ni rich shell, into mixed phases resembling gamma-FeNi3 and gamma-Fe3Ni2. This was possible in part by controlling surface diffusion via annealing temperature, and the enhanced diffusion at the many grain boundaries of the nanoparticle. Lattice expansion and phase change was characterized by powder X-ray diffraction (XRD), and composition was monitored by X-ray photoelectron spectroscopy (XPS). Of interest is that no phase precipitation was observed (i.e., heterostructure formation) in this system and the XRD results suggest that alloying composition or alloy gradient is uniform. This uniform alloying was considered using calculations of bulk diffusion and grain boundary diffusion for Fe and Ni self-diffusion, as well as Fe-Ni impurity diffusion is provided. In addition, alloying was further considered by calculations for Fe-Ni mixing enthalpy (Hmix) and phase segregation enthalpy (HSeg) using the Miedema model, which allowed for the consideration of alloying favorability or core-shell segregation in the alloying, respectively. Of particular interest is the formation of stable metal carbides compositions, which suggest that the typically inert organic self-assembled monolayer encapsulation can also be internalized.
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