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Cellular Uptake and Localization of Polymyxins in Renal Tubular Cells Using
Rationally Designed Fluorescent Probes
#MMPMID26392495
Yun B
; Azad MA
; Nowell CJ
; Nation RL
; Thompson PE
; Roberts KD
; Velkov T
; Li J
Antimicrob Agents Chemother
2015[Dec]; 59
(12
): 7489-96
PMID26392495
show ga
Polymyxins are cyclic lipopeptide antibiotics that serve as a last line of
defense against Gram-negative bacterial superbugs. However, the extensive
accumulation of polymyxins in renal tubular cells can lead to nephrotoxicity,
which is the major dose-limiting factor in clinical use. In order to gain further
insights into the mechanism of polymyxin-induced nephrotoxicity, we have
rationally designed novel fluorescent polymyxin probes to examine the
localization of polymyxins in rat renal tubular (NRK-52E) cells. Our design
strategy focused on incorporating a dansyl fluorophore at the hydrophobic centers
of the polymyxin core structure. To this end, four novel regioselectively labeled
monodansylated polymyxin B probes (MIPS-9541, MIPS-9542, MIPS-9543, and
MIPS-9544) were designed, synthesized, and screened for their antimicrobial
activities and apoptotic effects against rat kidney proximal tubular cells. On
the basis of the assessment of antimicrobial activities, cellular uptake, and
apoptotic effects on renal tubular cells, incorporation of a dansyl fluorophore
at either position 6 or 7 (MIPS-9543 and MIPS-9544, respectively) of the
polymyxin core structure appears to be an appropriate strategy for generating
representative fluorescent polymyxin probes to be utilized in intracellular
imaging and mechanistic studies. Furthermore, confocal imaging experiments
utilizing these probes showed evidence of partial colocalization of the
polymyxins with both the endoplasmic reticulum and mitochondria in rat renal
tubular cells. Our results highlight the value of these new fluorescent polymyxin
probes and provide further insights into the mechanism of polymyxin-induced
nephrotoxicity.
|Acinetobacter baumannii/drug effects/growth & development
[MESH]
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