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.

Polymyxin B in combination with doripenem against heteroresistant Acinetobacter baumannii : pharmacodynamics of new dosing strategies

“…This mathematical model described the rapid concentration-based killing of polymyxin B monotherapy well. As polymyxin B is Rao et al structurally similar to colistin with the exception of one amino acid residue, the D-leucine at position 6, 33 we based the combination mathematical model on the known mechanisms of action on the previously constructed colistin and doripenem mathematical models and applied them to polymyxin B. We similarly hypothesized that disruption of the bacterial outer membrane by binding to the lipid A of LPS resulted in increased permeability of the outer membrane that enhanced the penetration of doripenem and binding to its target site in the periplasmic membrane.…”

Blocking Peptidoglycan Recycling in Pseudomonas aeruginosa Attenuates Intrinsic Resistance to Fosfomycin

“…2,3,38 An example of such a well-known antibiotic that was reintroduced into clinical practice is fosfomycin. 6,24,26,34 This epoxide derivative of phosphonic acid (cis-1,2-epoxypropyl phosphonic acid) was discovered in 1969, originally named phosphonomycin, and was isolated from cultures of Streptomyces species.…”

Development of new polymyxin derivatives for multi-drug resistant Gram-negative infections

“…Polymyxins contain a number of cationic amino acid residues, consisting of α,γ-diaminobutyric acid (Dab). The characterized components of the clinically used polymyxins B and E (Colistin) have been recently reviewed 17,18 and are shown in Table 1. A representative structure (polymyxin B1, PMB1) is shown in Figure 1.…”