Novel inhibitors of Staphylococcus aureus RnpA that synergize with mupirocin
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Authors: Lounsbury, Nicole; Eidem, Tess; Colquhoun, Jennifer; Mateo, George; Abou-Gharbia, Magid; Dunman, Paul M.; Childers, Wayne E.
Abstract
We recently discovered RnpA as a promising new drug discovery target for methicillin-resistant S. aureus (MRSA). RnpA is an essential protein that is thought to perform two required cellular processes. As part of the RNA degrasome Rnpa mediates RNA degradation. In combination with rnpB it forms RNase P haloenzymes which are required for tRNA maturation. A high throughput screen identified RNPA2000 as an inhibitor of both RnpA-associated activities that displayed antibacterial activity against clinically relevant strains of S. aureus, including MRSA. Structure-activity studies aimed at improving potency and replacing the potentially metabotoxic furan moiety led to the identification of a number of more potent analogs. Many of these new analogs possessed overt cellular toxicity that precluded their use as antibiotics but two derivatives, including compound 5o, displayed an impressive synergy with mupirocin, an antibiotic used for decolonizing MSRA whose effectiveness has recently been jeopardized by bacterial resistance. Based on our results, compounds like 5o may ultimately find use in resensitizing mupirocin- resistant bacteria to mupirocin. (C) 2018 Elsevier Ltd. All rights reserved.
The Functions of the Mammalian Methionine Sulfoxide Reductase System and Related Diseases
ANTIOXIDANTS
Authors: Jiang, Beichen; Moskovitz, Jackob
Abstract
This review article describes and discusses the current knowledge on the general role of the methionine sulfoxide reductase (MSR) system and the particular role of MSR type A (MSRA) in mammals. A powerful tool to investigate the contribution of MSRA to molecular processes within a mammalian system/organism is the MSRA knockout. The deficiency of MSRA in this mouse model provides hints and evidence for this enzyme function in health and disease. Accordingly, the potential involvement of MSRA in the processes leading to neurodegenerative diseases, neurological disorders, cystic fibrosis, cancer, and hearing loss will be deliberated and evaluated.