Open AccessProbing the Penetration of Antimicrobial Polymyxin Lipopeptides into Gram-Negative Bacteria
Author(s) -
Zakuan Zainy Deris,
James Swarbrick,
Kade D. Roberts,
Mohammad Abul Kalam Azad,
Jesmin Akter,
Andrew S. Horne,
Roger L. Nation,
Kelly L. Rogers,
Phillip E. Thompson,
Tony Velkov,
Jian Li
Publication year - 2014
Publication title -
bioconjugate chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.279
H-Index - 172
eISSN - 1520-4812
pISSN - 1043-1802
DOI - 10.1021/bc500094d
Subject(s) - chemistry , antimicrobial , gram negative bacteria , polymyxin , microbiology and biotechnology , gram , penetration (warfare) , bacteria , polymyxin b , antibiotics , biochemistry , escherichia coli , organic chemistry , genetics , biology , gene , operations research , engineering
The dry antibiotic development pipeline coupled with the emergence of multidrug resistant Gram-negative 'superbugs' 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.