Pharmacology of polymyxins: new insights into an 'old' class of antibiotics

Abstract

Increasing antibiotic resistance in Gram-negative bacteria, particularly in Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae, presents a global medical challenge. No new antibiotics will be available for these 'superbugs' in the near future due to the dry antibiotic discovery pipeline. Colistin and polymyxin B are increasingly used as the last-line therapeutic options for treatment of infections caused by multidrug-resistant Gram-negative bacteria. This article surveys the significant progress over the last decade in understanding polymyxin chemistry, mechanisms of antibacterial activity and resistance, structure-activity relationships and pharmacokinetics/pharmacodynamics. In the 'Bad Bugs, No Drugs' era, we must pursue structure-activity relationship-based approaches to develop novel polymyxin-like lipopeptides targeting polymyxin-resistant Gram-negative 'superbugs'. Before new antibiotics become available, we must optimize the clinical use of polymyxins through the application of pharmacokinetic/pharmacodynamic principles, thereby minimizing the development of resistance.

Figure 1. Molecular models of the complex between polymyxin B₁ and the lipid A structure from Klebsiella pneumoniae

(A) The lipid A molecule is shown in space-filling representation and polymyxin B₁ is shown in stick representation. (B) The chemical structure of the lipid A molecule. (C) The key electrostatic interactions between positively charged Dab residues on polymyxin and the negatively charged lipid A phosphoresters. Dab: Diaminobutyric acid.

Figure 2. Key mechanisms of polymyxin resistance in Gram-negative bacteria

The pink shading indicates molecular determinants of polymyxin resistance. LPS: Lipopolysaccharide; NAG: N-acetylglucosamine; NAM: N-acetylmuramic acid; OMP: Outer membrane protein.

Figure 3. A selection of the reported medicinal chemistry modifications that have been made to the polymyxin core structural domains

The hydrophobic N-terminal fatty acyl chain (red), the linear tripeptide segment (green), the hydrophobic motif at positions 6 and 7 (blue) and the heptapeptide backbone (pink) are shown. Modifications to the diaminobutyric acid residue positions are not depicted.

Figure 4. Steady-state plasma concentration–time profiles of formed colistin in 105 critically ill patients (89 not on renal replacement, 12 on intermittent hemodialysis and four on continuous renal replacement therapy)

Physician-selected colistin methanesulfonate dosage intervals ranged from 8 to 24 h and hence the interdosing blood sampling interval spanned the same range. Reproduced with permission from [71].