Antibacterial Activity of Non-Cytotoxic, Amino Acid-Modified Polycationic Dendrimers against Pseudomonas aeruginosa and Other Non-Fermenting Gram-Negative Bacteria.

Anna Maria Schito,Silvana Alfei

doi:10.3390/polym12081818

Abstract

Due to the rapid increase of antimicrobial resistance with ensuring therapeutic failures, the purpose of this study was to identify novel synthetic molecules as alternatives to conventional available, but presently ineffective antibiotics. Variously structured cationic dendrimers previously reported have provided promising outcomes. However, the problem of their cytotoxicity towards eukaryotic cells has not been completely overcome. We have now investigated the antibacterial activities of three not cytotoxic cationic dendrimers (G5Ds: G5H, G5K, and G5HK) against several multidrug-resistant (MDR) clinical strains. All G5Ds displayed remarkable activity against MDR non-fermenting Gram-negative species such as P. aeruginosa, S. maltophilia, and A. baumannii (MICs = 0.5–33.2 µM). In particular, very low MIC values (0.5–2.1 µM) were observed for G5K, which proved to be more active than the potent colistin (2.1 versus 3.19 µM) against P. aeruginosa. Concerning its mechanism of action, in time-killing and turbidimetric studies, G5K displayed a rapid non-lytic bactericidal activity. Considering the absence of cytotoxicity of these new compounds and their potency, comparable or even higher than that provided by the dendrimers previously reported, G5Ds may be proposed as promising novel antibacterial agents capable of overcoming the alarming resistance rates of several nosocomial non-fermenting Gram-negative pathogens.

Highlights

IntroductionThe rapid and worldwide increase in antimicrobial resistance among bacterial pathogens, dramatically associated with therapeutic failures, has become a global concern urgently requiring alternative curative options [1]
The rapid and worldwide increase in antimicrobial resistance among bacterial pathogens, dramatically associated with therapeutic failures, has become a global concern urgently requiring alternative curative options [1].This situation applies to nosocomial pathogens that are responsible for a number of severe clinical conditions in immunocompromised and critically ill individuals [1]
Like other polymyxins, is a natural cationic antimicrobial cyclic peptide belonging to the class of antimicrobial cationic peptides (CAMPs) [3,4,5,6], able to display a remarkable potency against the non-fermenting species, usually causing nosocomial serious infections, such as P. aeruginosa, Acinetobacter spp., and S. maltophilia

Summary

Introduction

The rapid and worldwide increase in antimicrobial resistance among bacterial pathogens, dramatically associated with therapeutic failures, has become a global concern urgently requiring alternative curative options [1] This situation applies to nosocomial pathogens that are responsible for a number of severe clinical conditions in immunocompromised and critically ill individuals [1]. Aerobic non-fermenting Gram-negative bacilli such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia are emerging as clinically relevant superbugs, contributing significantly, with their worrying resistance levels, to numerous therapeutic failures [2] These species, in addition to their intrinsic resistance mechanisms, are rapidly becoming multidrug- or even pan-drug-resistant to most life-saving drugs, making the search for new antimicrobial agents urgent. Its widespread use is critically thwarted by its well-known nephro- and neurotoxicity [7]

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