作者: Metzger, Margaret ; Wan, Baojie ; Nguyen, Duc ; Feiner, Janaya ; Hossain, Akil ; Qader, Mallique ; Nugent, Angela ; Shetye, Gauri ; Franzblau, Scott ; Cuevas, Jake ; Kauffman, John ; Umesiri, Francis E

There is an urgent need to develop new anti-tuberculosis (anti-TB) drugs to tackle drug-resistant strains of Mycobacterium tuberculosis (M.tb). Whereas antimicrobial peptides (AMPs) have received attention because of their antibacterial properties, oligo-N-substituted glycines (peptoids) are now seen as favorable alternatives to AMPs because they are more stable and less vulnerable to protease degradation, less expensive to produce, and better suited to potential pharmaceutical adoption and development. In this work, therefore, we designed, synthesized, and screened 22 new α- and β-peptoids against drug susceptible M. tb strain H37Rv using the Microplate Alamar Blue assay (MABA) to evaluate minimum inhibitory concentration (MIC). Eight compounds (JC5, MM2, MM5, MM9, MM10, MM11, JF11, and JF13) had MICs of less than 10 μg/ml, the most potent of which were JC5 and MM2, with MICs of 1.48 μg/ml and 2.97 μg/ml, respectively. JC5 and MM2 also retained potency against strains mono-resistant to isoniazid and rifampin, and against five of the global M. tb clade representatives. Furthermore, peptoids JC5 and MM2 showed minimum bactericidal concentration (MBC) of 3.02 μg/ml and 5.48 μg/ml respectively. Intracellular activity by luminescence showed a macrophage EC90 of less than 10 μg/ml for both JC5 and MM2. In addition, both compounds showed remarkable narrow spectrum activity. Selectivity with respect to Vero cells was modest but sufficient to consider these classes of alpha and beta-peptoids as good leads for further development of anti-TB drugs.

2022-10-01·Clinical Lymphoma Myeloma and Leukemia

MM-010 Spontaneous Prosthetic Fracture in a Patient With Relapsed Multiple Myeloma

Article

作者: Enciso, Claudio Norberto ; Campestri, Reinaldo Manuel ; Freue, Julian Matias

CONTEXTPlasmacytomas are a form of plasma cell dyscrasia that present as a single mass of monoclonal plasma cells located either extramedullary or intraosseous. They can present as a solitary or multiple mass, either at diagnostic or in the context of a relapsed refractory patient. The latter scenario usually has a dismal prognosis. Bone fractures are frequent in patients with multiple myeloma (MM), sometimes requiring a surgical approach. Eventually, plasmacytomas can also develop surrounding a synthetic prothesis. Prosthetic fractures are a rare complication and usually present a challenging situation.OBJECTIVETo describe a case of prosthetic spontaneous fracture and exposure.DESIGNCase report.CASEA 52-year-old woman with a history of IgG kappa MM diagnosed in 2014 was admitted for severe back pain. Her MM was treated with CyBorD and consolidation with an autologous stem cell transplant. She also underwent surgery for a dorsal vertebral fracture at diagnosis. She had a first relapse in 2018 receiving a carfilzomib-based regimen as re-induction. In 2019 she had a 3° relapse with extensive bone disease and supraclavicular plasmacytoma in a lymph node. She received VTD-PACE for 3 cycles, achieving a partial response. At admission in 2020, dorsal x-ray showed prosthetic fracture. She also had a dorsal plasmacytoma. Her ECOG performance status was 4, and she received palliative care and a VAD regimen. The plasmacytoma continued to grow and ulcerated. Prothesis exposure was confirmed. Because of her bad performance status, she received palliative treatment.SUMMARY/CONCLUSIONExtramedullary relapses of plasma cell dyscrasias are usually aggressive and have a dismal prognosis. Rare reports and recommendations are available in the literature regarding the treatment of prosthetic fractures, and there is currently no consensus about the standard management for these patients. We present this case because of the rare incidence of prosthetic fractures.

2021-10-01·International Journal of Pharmaceutics2区 · 医学

Antimicrobial activity of synthetic antimicrobial peptides loaded in poly-Ɛ-caprolactone nanoparticles against mycobacteria and their functional synergy with rifampicin

2区 · 医学

Article

作者: Patil, Shripad A ; Verma, Rahul Kumar ; Gaur, Aparna ; Sharma, Neelesh ; Kumar, Vimal ; Singh, Amit Kumar ; Sharma, Ankur

Tuberculosis (TB) treatment has become a challenge because of the natural presence of multilayered cell wall rich in lipids which restrict antibiotic permeability within the bacteria. The development of mutations conferring resistance has aggravated the situation. Consequently, maximum pharmaceutical efforts are required to improve the treatment, and antimicrobial peptides (AMPs) with antimycobacterial activity can be exploited as a new treatment strategy against TB. The synergistic interaction between conventional antibiotics and AMPs has broadened its application landscape. To overcome peptide instability and bioavailability issues, encapsulation of these bioactive in biocompatible polymers was adopted. In this study, the effect of synthetic AMPs HHC-8 [KIWWWWRKR] and MM-10 [MLLKKLLKKM] encapsulated in poly (ε-caprolactone) nanoparticles (PCL-NPs) was evaluated against mycobacteria using REMA (Resazurin Microtiter Assay Plate) technique. PCL encapsulation allowed us to load the required amount of peptides, i.e. HHC-8 and MM-10, with an efficiency of ∼ 18.9 ± 5.24 and ∼ 21.1 ± 6.19 % respectively, and sphere size was around 376.5 ± 14.9 nm and 289.87 ± 17.98 nm for PCL-HHC-8-NPs and PCL-MM-10-NPs, respectively. Minimal degradation and sustained release of peptides from nanoparticles improved antimicrobial activity, decreasing the MIC₅₀ from 75 µg/ml to 18.75 µg/ml against M. smegmatis and from 75 µg/ml to 9 µg/ml against M. tuberculosis, respectively. The combinatorial MIC assays of encapsulated AMP with rifampicin antibiotics against M. smegmatis showed synergism between AMP-PCL-NPs and antibiotics with fractional inhibitory concentrations (FICs) around ∼ 0.09. The combinations of AMP NPs also demonstrated synergy against the mycobacteria. Our findings suggest that enhanced efficacy is due to protection offered by AMPs encapsulation resulting in augmentation of membrane permeation by AMPs and enhanced accumulation of antibiotics within mycobacteria resulting in synergy. The study findings might assist in the preclinical development of AMP for the fight against TB.

100 项与 MM-010 相关的药物交易

登录后查看更多信息