Abstract
Drug-resistant Pseudomonas aeruginosa is rapidly developing resulting in a serious global threat. Immunocompromised patients are specifically at risk, especially those with cystic fibrosis (CF). Novel metal complexes incorporating 1,10-phenanthroline (phen) ligands have previously demonstrated antibacterial and anti-biofilm effects against resistant P. aeruginosa from CF patients in vitro. Herein, we present the in vivo efficacy of {[Cu(3,6,9-tdda)(phen)2]·3H2O·EtOH}n (Cu-tdda-phen), {[Mn(3,6,9-tdda)(phen)2]·3H2O·EtOH}n (Mn-tdda-phen) and [Ag2(3,6,9-tdda)(phen)4]·EtOH (Ag-tdda-phen) (tddaH2 = 3,6,9-trioxaundecanedioic acid). Individual treatments of these metal-tdda-phen complexes and in combination with the established antibiotic gentamicin were evaluated in vivo in larvae of Galleria mellonella infected with clinical isolates and laboratory strains of P. aeruginosa. G. mellonella were able to tolerate all test complexes up to 10 µg/larva. In addition, the immune response was affected by stimulation of immune cells (hemocytes) and genes that encode for immune-related peptides, specifically transferrin and inducible metallo-proteinase inhibitor. The amalgamation of metal-tdda-phen complexes and gentamicin further intensified this response at lower concentrations, clearing a P. aeruginosa infection that were previously resistant to gentamicin alone. Therefore this work highlights the anti-pseudomonal capabilities of metal-tdda-phen complexes alone and combined with gentamicin in an in vivo model.
Highlights
Introduction iationsAntimicrobial resistance (AMR) endangers the effective prevention and treatment of an expanding scope of infections caused by microorganisms that are no longer susceptible to the standard therapies used to manage them [1]
We recently demonstrated the activity profiles of manganese(II), copper(II), and silver(I) complexes incorporating 1,10-phenanthroline and 3,6,9-trioxaundecanedioate against P. aeruginosa strains isolated from the lungs of cystic fibrosis (CF) patients [27]
Pseudomonas aeruginosa (CF1, CF2, and CF3) isolated from cystic fibrosis (CF) patients at local Irish hospitals, with multidrug-resistant mechanisms [27], and standard laboratory strains ATCC 27853 and PAO1 were used in this study
Summary
Antimicrobial resistance (AMR) endangers the effective prevention and treatment of an expanding scope of infections caused by microorganisms that are no longer susceptible to the standard therapies used to manage them [1]. This presents a widespread and urgent threat to global health. Of particular concern are Gram-negative bacteria with surging resistance profiles especially to the last line of antibiotics [2]. The Gram-negative human pathogen, Pseudomonas aeruginosa, is a noteworthy contributor to elevated AMR prevalence and is frequently isolated from a diverse range of acute, chronic, and biofilm-associated infections.
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