Polymyxins, the last-resort antibiotics: Mode of action, resistance emergence, and potential solutions

Abstract

Infections caused by multi-drug resistant (MDR) bacterial pathogens are a leading cause of mortality and morbidity across the world. Indiscriminate use of broad-spectrum antibiotics has seriously affected this situation. With the diminishing discovery of novel antibiotics, new treatment methods are urgently required to combat MDR pathogens. Polymyxins, the cationic lipopeptide antibiotics, discovered more than half a century ago, are considered to be the last-line of antibiotics available at the moment. This antibiotic shows a great bactericidal effect against Gram-negative bacteria. Polymyxins primarily target the bacterial membrane and disrupt them, causing lethality. Because of their membrane interacting mode of action, polymyxins cause nephrotoxicity and neurotoxicity in humans, limiting their usability. However, recent modifications in their chemical structure have been able to reduce the toxic effects. The development of better dosing regimens has also helped in getting better clinical outcomes in the infections caused by MDR pathogens. Since the mid-1990s the use of polymyxins has increased manifold in clinical settings, resulting in the emergence of polymyxin-resistant strains. The risk posed by the polymyxin-resistant nosocomial pathogens such as the Enterobacteriaceae group, Pseudomonas aeruginosa , and Acinetobacter baumannii, etc. is very serious considering these pathogens are resistant to almost all available antibacterial drugs. In this review article, the mode of action of the polymyxins and the genetic regulatory mechanism responsible for the emergence of resistance are discussed. Specifically, this review aims to update our current understanding in the field and suggest possible solutions that can be pursued for future antibiotic development. As polymyxins primarily target the bacterial membranes, resistance to polymyxins arises primarily by the modification of the lipopolysaccharides (LPS) in the outer membrane (OM). The LPS modification pathways are largely regulated by the bacterial two-component signal transduction (TCS) systems. Therefore, targeting or modulating the TCS signalling mechanisms can be pursued as an alternative to treat the infections caused by polymyxin-resistant MDR pathogens. In this review article, this aspect is also highlighted.

Population Pharmacokinetics of Colistin Sulfate in Critically Ill Patients: Exposure and Clinical Efficacy

“…Polymyxins (colistin and polymyxin B) are old antimicrobials, which have been used clinically since the late 1960s, acting against Gram-negative bacteria such as Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli ( Evans et al, 1999 ; Mohapatra et al, 2021 ). However, the clinical use of polymyxins has been restricted due to their side effects, such as neurotoxicity and nephrotoxicity.…”

Impact of a Novel Anticoccidial Analogue on Systemic Staphylococcus aureus Infection in a Bioluminescent Mouse Model

“…The outer membrane is a distinctive feature of GNB that provides a barrier protecting GNB from exposure to unwanted chemical compounds, resulting in limited treatment options [ 12 , 41 ]. Among several proposed therapies for the further treatment of GNB infections [ 42 , 43 ], a combination of colistin with other antibiotics is considered a potential approach associated with overcoming the outer membrane permeability barrier, a broader antibacterial spectrum, synergistic effects and reduced risk for emerging resistance during therapy [ 20 , 44 , 45 ]. In addition, many studies have demonstrated that, in contrast to monotherapy, combination therapy may enhance antimicrobial effects and provide synergism [ 46 , 47 , 48 , 49 , 50 ].…”

“…However, these antibiotics are far from ideal therapeutic options to fully combat the emergence of MDR GNB infection [ 18 ]. Currently, polymyxins (such as polymyxin B (PMB) and colistin) are considered last-resort antibiotics for the treatment of MDR GNB infections particularly due to their specific targeting of the outer membrane [ 19 , 20 , 21 ]. Nonetheless, resistance to polymyxins is emerging via multiple mechanisms [ 19 , 20 , 22 ].…”

“…Currently, polymyxins (such as polymyxin B (PMB) and colistin) are considered last-resort antibiotics for the treatment of MDR GNB infections particularly due to their specific targeting of the outer membrane [ 19 , 20 , 21 ]. Nonetheless, resistance to polymyxins is emerging via multiple mechanisms [ 19 , 20 , 22 ]. Moreover, many studies have reported that the use of polymyxins is associated with nephrotoxicity, neurotoxicity and neuromuscular blockade [ 23 ].…”

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

“…Whilst there is overwhelming evidence that polymyxins cause membrane disruption [23,32,33], additional mechanisms have been proposed to contribute to bacterial killing. These have been summarized in detail elsewhere [44] and so only a brief overview is provided here. Colistin, and other polymyxins, have been found to directly inhibit the enzymatic activity of the respiratory enzyme NDH-2 from E. coli, K. pneumoniae and A. baumannii [45].…”