Polymyxin and lipopeptide antibiotics: membrane-targeting drugs of last resort

Abstract

The polymyxin and lipopeptide classes of antibiotics are membrane-targeting drugs of last resort used to treat infections caused by multi-drug-resistant pathogens. Despite similar structures, these two antibiotic classes have distinct modes of action and clinical uses. The polymyxins target lipopolysaccharide in the membranes of most Gram-negative species and are often used to treat infections caused by carbapenem-resistant species such as Escherichia coli, Acinetobacter baumannii and Pseudomonas aeruginosa. By contrast, the lipopeptide daptomycin requires membrane phosphatidylglycerol for activity and is only used to treat infections caused by drug-resistant Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. However, despite having distinct targets, both antibiotic classes cause membrane disruption, are potently bactericidal in vitro and share similarities in resistance mechanisms. Furthermore, there are concerns about the efficacy of these antibiotics, and there is increasing interest in using both polymyxins and daptomycin in combination therapies to improve patient outcomes. In this review article, we will explore what is known about these distinct but structurally similar classes of antibiotics, discuss recent advances in the field and highlight remaining gaps in our knowledge.

Keywords: antibiotic; colistin; daptomycin; lipopeptide; polymyxin; resistance.

Fig. 1.

Structures of daptomycin and polymyxin B/colistin. The structure of daptomycin is shown in (a) and the structure of polymyxin B/colistin in (b), with differences between the two polymyxins indicated. In both cases, the peptide ring is shown in red, the exocyclic tripeptide in purple and the lipid tail in green, while the ester bond of daptomycin is shown in light blue.

Fig. 2.

Current model for the mechanism of action of polymyxin antibiotics. The cationic peptide ring of the polymyxin (colistin) interacts with lipid A of LPS (1), leading to displacement of the cation bridges and weakening of the outer leaflet of the outer membrane (OM) (2). The lipid tail of colistin inserts into the outer leaflet, further weakening the OM (3). The polymyxin then traverses the OM via self-promoted uptake and enters the periplasm (4). The polymyxin then engages LPS in the cytoplasmic membrane (5) before it is transported to the OM by the multi-component Lpt system (in red), leading to disruption of this structure, escape of cytoplasmic contents, and possibly downstream effects such as production of reactive oxygen species, followed by bacterial death and lysis (6).

Fig. 3.

Proposed mechanisms by which daptomycin disrupts membrane integrity and cell wall biosynthesis. Daptomycin disrupts the membrane by forming oligomeric complexes with phosphatidylglycerol, leading to leakage of ions and ATP out of the cell (a). Daptomycin binding at division septa leads to inhibition of cell wall synthesis via two proposed mechanisms (b). In the first model, daptomycin binds to fluid regions of the membrane, causing membrane rigidification. This leads to the mislocalization of peripheral membrane proteins involved in peptidoglycan synthesis to the cytoplasm, decreasing cell wall synthesis. In the second model, daptomycin binds to a complex consisting of phosphatidylglycerol, calcium ions and membrane-bound cell wall precursors, inhibiting the translocation of peptidoglycan precursors across the membrane. These two mechanisms are not mutually exclusive and may act synergistically to inhibit cell wall biosynthesis.

Fig. 4.

Cell membrane of daptomycin-susceptible (left) and non-susceptible (right) S. aureus . Daptomycin non-susceptible strains have been observed to have decreased phosphatidylglycerol and increased cardiolipin, lysylphosphatidylglycerol and staphyloxanthin compared to susceptible strains.

Fig. 5.

Cell wall of daptomycin-susceptible (left) and non-susceptible (right) S. aureus . Daptomycin non-susceptible strains have been observed to have increased levels of d-alanylated wall teichoic acid (WTA) and thicker cell walls than susceptible strains.