The Hybrid Antibiotic Thiomarinol A Overcomes Intrinsic Resistance in Escherichia coli Using a Privileged Dithiolopyrrolone Moiety

• DOI: 10.1021/acsinfecdis.3c00504
• Publication Date: 2024-01-16T12:04:21Z
• Authors: Rachel M. Johnson; Kelin Li; Xiaoyan Chen; Gina L. Morgan; Jeffrey Aubé; Bo Li
• Keywords: Moiety

An impermeable outer membrane and multidrug efflux pumps work in concert to provide Gram-negative bacteria with intrinsic resistance against many antibiotics. These mechanisms reduce the intracellular concentrations of antibiotics render them ineffective. The natural product thiomarinol A combines holothin, a dithiolopyrrolone antibiotic, marinolic acid A, close analogue mupirocin. hybridity converts mupirocin scaffold from inhibiting Gram-positive both -negative bacteria. We found that accumulates significantly more than within bacterium Escherichia coli, likely contributing its broad-spectrum activity. Antibiotic susceptibility testing E. coli mutants reveals overcomes inactive. Structure-activity relationship studies suggest is privileged moiety for improving accumulation antibiotic activity without compromising binding isoleucyl-tRNA synthetase. also highlight required but not sufficient Our role overcoming provides starting point designing dual-acting high-accumulating hybrid