Small Molecule Downregulation of PmrAB Reverses Lipid A Modification and Breaks Colistin Resistance

详细信息    查看全文

• 作者：Tyler L. Harris ; Roberta J. Worthington ; Lauren E. Hittle ; Daniel V. Zurawski ; Robert K. Ernst ; Christian Melander
• 刊名：ACS Chemical Biology
• 出版年：2014
• 出版时间：January 17, 2014
• 年：2014
• 卷：9
• 期：1
• 页码：122-127
• 全文大小：272K
• ISSN：1554-8937

文摘

Infections caused by multi-drug resistant bacteria, particularly Gram-negative bacteria, are an ever-increasing problem. While the development of new antibiotics remains one option in the fight against bacteria that have become resistant to currently available antibiotics, an attractive alternative is the development of adjuvant therapeutics that restore the efficacy of existing antibiotics. We report a small molecule adjuvant that suppresses colistin resistance in multidrug resistant Acinetobacter baumannii and Klebsiella pneumoniae by interfering with the expression of a two-component system. The compound downregulates the pmrCAB operon and reverses phosphoethanolamine modification of lipid A responsible for colistin resistance. Furthermore, colistin-susceptible and colistin-resistant bacteria do not evolve resistance to combination treatment. This represents the first definitive example of a compound that breaks antibiotic resistance by directly modulating two-component system activity.