Polymyxins and Bacterial Membranes: A Review of Antibacterial Activity and Mechanisms of Resistance

Abstract

Following their initial discovery in the 1940s, polymyxin antibiotics fell into disfavor due to their potential clinical toxicity, especially nephrotoxicity. However, the dry antibiotic development pipeline, together with the rising global prevalence of infections caused by multidrug-resistant (MDR) Gram-negative bacteria have both rejuvenated clinical interest in these polypeptide antibiotics. Parallel to the revival of their use, investigations into the mechanisms of action and resistance to polymyxins have intensified. With an initial known effect on biological membranes, research has uncovered the detailed molecular and chemical interactions that polymyxins have with Gram-negative outer membranes and lipopolysaccharide structure. In addition, genetic and epidemiological studies have revealed the basis of resistance to these agents. Nowadays, resistance to polymyxins in MDR Gram-negative pathogens is well elucidated, with chromosomal as well as plasmid-encoded, transferrable pathways. The aims of the current review are to highlight the important chemical, microbiological, and pharmacological properties of polymyxins, to discuss their mechanistic effects on bacterial membranes, and to revise the current knowledge about Gram-negative acquired resistance to these agents. Finally, recent research, directed towards new perspectives for improving these old agents utilized in the 21st century, to combat drug-resistant pathogens, is summarized.

Antibiotic Resistance and Phylogeny of Pseudomonas spp. Isolated over Three Decades from Chicken Meat in the Norwegian Food Chain

“…The emerging transferable plasmid-encoded colistin resistance determinants (mrc) were, however, not detected. Colistin resistance is largely unknown in non-aeruginosa Pseudomonas although both acquired and intrinsic resistance have been reported, including a naturally resistant Pseudomonas species (P. mallei; [58]). Additional resistance mechanisms include activation of the regulatory gene operon phoPQ and further activation of arnA, leading to lipid A modifications associated with colistin resistance [59].…”

“…The arnA gene was present in 30 isolates while the phoPQ operon was present in only nine of the 19 colistin-resistant WGS isolates according to annotations by Prokka. Overexpression of multidrug efflux systems (e.g., AcrAB-TolC, NorM, EmrAB) and downregulation of porin OprD have also been reported as colistin resistance mechanisms (see review by Moubareck [58] and references therein).…”

Caspofungin and Polymyxin B Reduce the Cell Viability and Total Biomass of Mixed Biofilms of Carbapenem-Resistant Pseudomonas aeruginosa and Candida spp.

“…The action of PMB on fungal cells is poorly understood, and some studies suggest effects on the fungal membrane (Zhai et al, 2010;Yousfi et al, 2019). This explanation could be plausible if we consider that polymyxins binds to the outer membrane of Gram-negative bacteria, where it complexes avidly with lipopolysaccharides showing an outer membrane-disorganizing action (Ayoub Moubareck, 2020). This primary damage in the outer membrane allows polymyxins to achieve the cytoplasmic membrane, where it causes leakage of cytoplasmic contents leading to bacterial death.…”

“…Thus, it is evident that the membrane permeability changes immediately on contact with the drug. However, since activity of polymyxins is antagonized by Mg 2+ and Ca 2+ could be assumed that part of the action of this antibiotic is also due to the competitively displacing Mg 2+ or Ca 2+ from the negatively charged phosphate groups of membrane lipids (Ayoub Moubareck, 2020). Therefore, once cationic polymyxins interact with negatively charged moieties at the outer microbial cell structure, the negative charge of the fungal wall, conferred by mannoproteins that harbor phosphate groups (Ruiz-Herrera et al, 2006;Yousfi et al, 2019;Garcia-Rubio et al, 2020), would allow the coverage of fungal cells by polymyxins generating a positive charge on the cell surface with eventual disruption leading to antimicrobial effects.…”

Enhanced Antimicrobial and Antibiofilm Effect of New Colistin-Loaded Human Albumin Nanoparticles

“…Moreover, some bacteria such as Serratia , Proteus and Burkholderia spp. are intrinsically resistant to Col by LPS modification [ 6 , 7 ].…”