Probing the Penetration of Antimicrobial Polymyxin Lipopeptides into Gram-Negative Bacteria
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- 作者：Zakuan Z. Deris ; James D. Swarbrick ; Kade D. Roberts ; Mohammad A. K. Azad ; Jesmin Akter ; Andrew. S. Horne ; Roger L. Nation ; Kelly L. Rogers ; Phillip E. Thompson ; Tony Velkov ; Jian Li
- 刊名：Bioconjugate Chemistry
- 出版年：2014
- 出版时间：April 16, 2014
- 年：2014
- 卷：25
- 期：4
- 页码：750-760
- 全文大小：524K
- 年卷期：v.25,no.4(April 16, 2014)
- ISSN：1520-4812
文摘
The dry antibiotic development pipeline coupled with the emergence of multidrug resistant Gram-negative 鈥榮uperbugs鈥?has driven the revival of the polymyxin lipopeptide antibiotics. Polymyxin resistance implies a total lack of antibiotics for the treatment of life-threatening infections. The lack of molecular imaging probes that possess native polymyxin-like antibacterial activity is a barrier to understanding the resistance mechanisms and the development of a new generation of polymyxin lipopeptides. Here we report the regioselective modification of the polymyxin B core scaffold at the N-terminus with the dansyl fluorophore to generate an active probe that mimics polymyxin B pharmacologically. Time-lapse laser scanning confocal microscopy imaging of the penetration of probe (1) into Gram-negative bacterial cells revealed that the probe initially accumulates in the outer membrane and subsequently penetrates into the inner membrane and finally the cytoplasm. The implementation of this polymyxin-mimetic probe will advance the development of platforms for the discovery of novel polymyxin lipopeptides with efficacy against polymyxin-resistant strains.