Circumventing colistin resistance by combining colistin and antimicrobial peptides to kill colistin-resistant and multidrug-resistant Gram-negative bacteria

Abstract

Objectives: Colistin is a ‘last-line’ antibiotic used to treat multidrug-resistant Gram-negative bacteria, but colistin resistance has emerged. Colistin normally binds to the lipid A moiety on the bacterial outer membrane, where it then destroys the bacterial membrane. Mobilize colistin resistance (MCR, encoded by mcr-1 and others) is a phosphoethanolamine transferase that modifies lipid A, preventing colistin binding. We hypothesized that combining pore-forming AMPs and colistin will circumvent this mechanism and reduce the minimum inhibitory concentration (MIC) of colistin for both colistin- and multidrug-resistant Gram-negative bacteria. Methods: In vitro cultures were incubated for 18 h after combining bacteria ( Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa ) with serially diluted colistin and a fixed concentration of peptide MSI-78 or OTD-244. Results: When combined with either peptide, the colistin MIC decreased more than 4-fold for 88% of all tested isolates ( n = 17; range, 4–64-fold reduction) and for 75% of colistin-resistant isolates ( n = 8; range, 4–64-fold reduction). The concentrations used had no effect on red blood cells based on a conventional haemolysis assay. Conclusions: These findings are consistent with two membrane-damaging compounds having an additive effect on bacterial killing. Combining antimicrobial peptides with colistin is a promising strategy for bypassing MCR-mediated colistin resistance, but also for improving the susceptibility of other Gram-negative bacteria while potentially reducing the therapeutic concentration of colistin needed to treat infections.

Synergistic effect of two antimicrobial peptides, BP203 and MAP-0403 J-2 with conventional antibiotics against colistin-resistant Escherichia coli and Klebsiella pneumoniae clinical isolates

“…In the case of MAP-0403 J-2, it might contribute to potentiating the membrane perturbing activity of colistin, leading to microbial death at lower concentrations than those needed by the single agent. The synergistic effects of some AMPs and colistin against colistin-resistant E. coli have been elucidated in previously described [54][55][56]. Of note, our results also suggested that the synergistic effects of each AMP with different antibiotics could depend on bacterial species.…”

“…Interestingly, MAP-0403 J-2 acts synergistically with colistin against most colistin-resistant E. coli isolates, but BP203 could not synergize with colistin against all E. coli isolates. This finding implied that the specific binding mechanism to bacterial membrane likely varies for different AMPs; therefore, modification of lipid A and other membrane moieties might not universally confer resistance to all AMPs [54]. In the case of MAP-0403 J-2, it might contribute to potentiating the membrane perturbing activity of colistin, leading to microbial death at lower concentrations than those needed by the single agent.…”

Synergistic antibacterial effects of colistin in combination with aminoglycoside, carbapenems, cephalosporins, fluoroquinolones, tetracyclines, fosfomycin, and piperacillin on multidrug resistant Klebsiella pneumoniae isolates

“…As the fight against multidrug resistance continues, concerted efforts by agencies, health care systems and biomedical scientist are restlessly exploring possible alternatives that might suffice pending the discovery and development of novel antibacterial agents that could effectively curb the spread of antibiotics resistance. The use of antibiotics combinations [13][14][15], efflux pump inhibitors [16][17][18], and resistance modifying agents [19,20] are suggested as temporary control measures to reverse microbial resistance or enhance the inactivation of resistant bacterial isolates. Antibiotics combination therapy is proposed as a reliable option with demonstrated results against multidrug resistant bacterial isolates.…”

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 ].…”