Design and Evaluation of Novel Polymyxin Fluorescent Probes.

Bo Yun,Tony Velkov,Jian Li,Kade Roberts,Roger Nation,Philip Thompson

doi:10.3390/s17112598

Abstract

Polymyxins (polymyxin B and colistin) are cyclic lipopeptide antibiotics that serve as a last-line defence against Gram-negative “superbugs”. In the present study, two novel fluorescent polymyxin probes were designed through regio-selective modifications of the polymyxin B core structure at the N-terminus and the hydrophobic motif at positions 6 and 7. The resulting probes, FADDI-285 and FADDI-286 demonstrated comparable antibacterial activity (MICs 2–8 mg/L) to polymyxin B and colistin (MICs 0.5–8 mg/L) against a panel of gram-negative clinical isolates of Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. These probes should prove to be of considerable utility for imaging cellular uptake and mechanistic investigations of these important last-line antibiotics.

Highlights

Over the past two decades there has been a pronounced increase in the emergence of multidrug-resistant (MDR) Gram-negative “superbugs”, leading to serious infections that are resistant to almost all currently available antibiotics [1]
N-terminal fatty acyl group of polymyxin B was substituted with dansylglycine-octanylglycine (Figure 1) [11]
The hydrophobic dansyl group was utilized as the fluorophore, as its comparatively small size relative to other fluorophores would help to reduce the likelihood of negative steric effects on the polymyxin pharmacophore [7]

Summary

Introduction

Over the past two decades there has been a pronounced increase in the emergence of multidrug-resistant (MDR) Gram-negative “superbugs”, leading to serious infections that are resistant to almost all currently available antibiotics [1]. The dire situation is perpetuated by a lack of novel antibiotics in the developmental pipeline, leaving the world in a vulnerable state against these life-threatening infections [1]. This “perfect storm” has led to the revival of the polymyxin class of antibiotics, polymyxin B and E (the latter known as colistin), as a last line of defence against. MDR Gram-negative “superbugs” [2] Despite their excellent antibacterial activity, the use of polymyxins has largely been limited by a high incidence of nephrotoxicity among patients receiving these antibiotics [3,4,5,6]. The two polymyxins used clinically, polymyxin B and colistin, are differentiated by a single hydrophobic residue at position 6: D-leucine in colistin and

Methods

Results

Conclusion