Effective Strategy Targeting Polymyxin-Resistant Gram-Negative Pathogens: Polymyxin B in Combination with the Selective Serotonin Reuptake Inhibitor Sertraline

Abstract

This study aimed to investigate synergistic antibacterial activity of polymyxin B in combination with the selective serotonin reuptake inhibitor, sertraline, against the Gram-negative pathogens Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The combination of polymyxin B and sertraline showed synergistic antibacterial activity in checkerboard and static time-kill assays at clinically relevant concentrations against both polymyxin-susceptible and polymyxin-resistant isolates. The potential antimicrobial mode of action of the combination was investigated against P. aeruginosa FADDI-PA024 using untargeted metabolomics alongside scanning and transmission electron microscopy (EM). Scanning and transmission EM revealed that the polymyxin B and sertraline combination resulted in greater damage to the bacterial cell compared to each drug alone. Metabolomics results showed that the combination significantly affected the bacterial ability to remodel its outer membrane. This was reflected by the major perturbation of glycerophospholipids and fatty acids and the pantothenate and coenzyme A (CoA) pathways, which feed fatty acid elongation (e.g., trans-hexadec-2-enoyl-CoA) as well as inhibit the biosynthesis of lipopolysaccharide and peptidoglycan. The combination also inhibited the polymyxin resistance phosphoethanolamine (pEtN) lipid A modification pathway, indicated by the declined levels of phosphoethanolamine. In summary, the present study highlights the potential possibilities of a polymyxin–sertraline combination for the treatment of infections caused by multidrug resistant Gram-negative bacteria such as central nervous system (CNS) infections via direct intraventricular/intrathecal delivery.

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

“…The recent trending strategy in testing FDA-approved medications that have no antibacterial activity in combination with antibacterials to enhance the latter’s effect is being applied to polymyxins. In a truly ground-breaking approach, researchers from Australia found that a combination of polymyxin B and the selective serotonin reuptake inhibitor, sertraline, resulted in greater damage to P. aeruginosa , highlighting the likely possibilities of this combination for the treatment of central nervous system infections [ 214 ]. Moreover, the experimental antitumor compound PFK-158 was found to enhance the activity of colistin and delay resistance emergence in mice infected with Enterobacteriaceae [ 215 ].…”

In Vitro Evaluation of Antimicrobial Peptide Tridecaptin M in Combination with Other Antibiotics against Multidrug Resistant Acinetobacter baumannii

“…This compound might cause some modifications to the bacterial cellular components which are crucial for synergy as reported for one of the compounds recently [ 45 ]. Additionally, polymyxin and serotonin reuptake inhibitor sertraline combination was shown to affect membrane biogenesis [ 46 ]. The exact mechanism responsible for this synergy obtained with tridecaptin M needs further investigation and is beyond the scope of this study.…”

Nitrite Promotes ROS Production to Potentiate Cefoperazone-Sulbactam-Mediated Elimination to Lab-Evolved and Clinical-Evolved Pseudomonas aeruginosa

“…The primary mechanisms with tamoxifen involve disruption of cell envelope biogenesis and inhibition of lipopolysaccharide (LPS) modifications. In combination with sertraline, polymyxin B impairs glycerophospholipids and fatty acids and the pantothenate and coenzyme A pathways ( 6 , 7 ). These studies may provide valuable information about metabolic pathways leading to an understanding of the adaptations of bacterial strains to antibiotic stress.…”