Potential Strategies for the Eradication of Multidrug-Resistant Gram-Negative Bacterial Infections

Abstract

Antimicrobial resistance is one of the leading threats to society. The increasing burden of multidrug-resistant Gram-negative infection is particularly concerning as such bacteria are demonstrating resistance to nearly all currently licensed therapies. Various strategies have been hypothesized to treat multidrug-resistant Gram-negative infections including: targeting the Gram-negative outer membrane; neutralization of lipopolysaccharide; inhibition of bacterial efflux pumps and prevention of protein folding. Silver and silver nanoparticles, fusogenic liposomes and nanotubes are potential strategies for extending the activity of licensed, Gram-positive selective, antibiotics to Gram-negatives. This may serve as a strategy to fill the current void in pharmaceutical development in the short term. This review outlines the most promising strategies that could be implemented to solve the threat of multidrug-resistant Gram-negative infections.

Self-assembling diphenylalanine peptide nanotubes selectively eradicate bacterial biofilm infection

“…Gram-negative bacteria possess an extra outer lipopolysaccharide membrane that limits influx and uptake of antibiotic molecules [31]. This outer membrane has proven to be a major obstacle in antibiotic uptake, treatment efficacy and drug development within Gram-negative infections [32]. The ability of the most promising peptide nanotube, NH2-FF-COOH, to permeate the outer lipopolysaccharide membrane was studied using NPN as a fluorescent probe to indicate whether the Gramnegative membrane is compromised in E.coli and P. aeruginosa [26].…”

Tristemma hirtumand Five Other Cameroonian Edible Plants with Weak or No Antibacterial Effects Modulate the Activities of Antibiotics against Gram-Negative Multidrug-Resistant Phenotypes

“…During the last decade, the number of multidrug-resistant (MDR) pathogenic bacteria has dramatically increased all over the world [ 1 – 3 ]. The burden of MDR Gram-negative bacteria infections is particularly concerning because such bacteria are demonstrating resistance to nearly all currently licensed antibiotics [ 2 , 4 ]. As a consequence, inadequate empirical antibacterial therapy of severe infections caused by MDR Enterobacteriaceae as well as Pseudomonas aeruginosa and Acinetobacter baumannii has been associated with increased morbidity and mortality [ 5 , 6 ].…”

“…As a consequence, inadequate empirical antibacterial therapy of severe infections caused by MDR Enterobacteriaceae as well as Pseudomonas aeruginosa and Acinetobacter baumannii has been associated with increased morbidity and mortality [ 5 , 6 ]. In this alarming scenario, the discovery of novel drugs that could provide clinical efficacy against MDR Gram-negative pathogens remains one of the keys to successfully overcome the tide of resistance [ 1 , 4 ]. Targeting MDR systems as efflux in antibiotic resistant pathogens seems to be one of the most important existing strategies [ 4 , 7 ].…”

Peptide Nanomaterials as Future Antimicrobial Technologies

“…An easy-to-synthesize low-molecular-weight peptide has the potential to widely be exploited as immune adjuvants for vaccines, 3D cell culture, cell and bioactive molecule (e.g., genes) delivery, bioimaging agents and diagnostics. Peptide nanotube platforms have huge potential as drug delivery platforms for transversing biological barriers, for example, the outer membrane of Gram-negative bacteria, mimicking the value of their carbon counterparts in terms of therapeutic applications but with improved chemical functionality for drug conjugation and reduced toxicity concerns [20]. Their value may lie in encapsulating and extending the spectrum of activity of licensed Gram-positive selective antibiotics for delivery across the outer membrane of Gram-negative bacteria including Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and…”