Macrocyclization has been frequently utilized for optimizing peptide or peptidomimetic-based compounds. In an attempt to obtain potent, metabolically stable, and orally available proteasome inhibitors, 30 oprozomib-derived macrocyclic peptides with structural diversity in their N-terminus and linker were successively designed and synthesized for structure− activity relationship (SAR) studies. As a consequence, the macrocyclic peptides with N-methyl-pyrazole (24p, 24x), imidazole (24t), and pyrazole (24v) as their respective N-termini exhibited favorable in vitro activity and metabolic stability, which translated into their potent in vivo proteasome inhibitory activity after oral administration. In particular, compound 24v, as the most distinguished one among this series, displayed excellent chymotrypsin-like (ChT-L, β5) inhibitory potency (IC 50 = 16 nM), low nanomolar antiproliferative activity against all three of the tested cell lines, and superior metabolic stability in mouse liver microsome (MLM), as well as favorable inhibition against ChT-L compared to that of oprozomib in BABL/c mice following po administration at a comparatively low dose, thereby representing a promising candidate for further development.
Introduction: Bloodstream infection (BSI) is associated with high mortality rates. Mycoplasma hominis, which rarely causes extragenital infections, has been shown to induce BSI and presents a clinical diagnostic and therapeutic challenge. Methods: In this study, we investigated the clinical characteristics, antibiotic resistance, and multilocus sequence typing (MLST) of eight BSI cases caused by M. hominis in South China from January 2018 to October 2021. Results: Underlying immunosuppression and genitourinary tract surgery are important risk factors for M. hominis BSI. The most prevalent clinical symptoms and signs were fever. Additional findings included elevated neutrophil count and C-reactive protein level. Furthermore, in this study, all the patients had erythrocytopenia. M. hominis harbored the highest rate of resistance to levofloxacin (75.0%), followed by sparfloxacin (50.0%), and gatifloxacin (37.5%). gyrA S153L was the most frequent mutation in levofloxacin-resistant strains, followed by parC S91I. parC K144R may be related to resistance to gatifloxacin and sparfloxacin. Eight strains showed sensitivity to all the other antibiotics analyzed (doxycycline, minocycline, josamycin, and clindamycin). MLST was performed in seven isolates, and seven new sequence types were described. We compared our isolates with all M. hominis strains from the PubMLST database, and one major clonal complex and eight singletons were identified. Conclusions: Our study clarified and expanded the clinical features and antibiotic resistance of M. hominis BSI. These findings are useful for the clinical diagnosis and control of M. hominis BSI.
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