The activity of a Ga(III) catecholate complex against Aspergillus fumigatus in conditions mimicking cystic fibrosis lung and inhaled formulations for its pulmonary administration.

Azole-resistant Aspergillus fumigatus (A. fumigatus) is an emerging worldwide pathogen. Pulmonary aspergillosis primarily affects severely immunocompromised patients and is also a particularly critical condition for cystic fibrosis (CF) patients.

Quantitative proteomic analysis reveals Ga(III) polypyridyl catecholate complexes disrupt Aspergillus fumigatus mitochondrial function.

Infections caused by the airborne fungal pathogen, Aspergillus fumigatus, are increasing in severity due to growing numbers of immunocompromised individuals and the increasing incidence of antifungal drug resistance, exacerbating treatment challenges. Gallium has proven to be a strong candidate in the fight against microbial pathogens due to its iron-mimicking capability and substitution of Ga(III) in place of Fe(III), disrupting iron-dependent pathways. Since the antimicrobial properties of 2,2'-bipyridine and derivatives have been previously reported, we assessed the in vitro activity and proteomic effects of a recently reported heteroleptic Ga(III) polypyridyl catecholate compound against A.

Synthesis, characterisation and antibacterial activity of novel Ga(III) polypyridyl catecholate complexes.

Ga(III) polypyridyl catecholate complexes of type [Ga(bipy)(O,O)](NO) or [Ga(phen)(O,O)](NO) respectively were readily synthesised on reaction of Ga(NO) in methanol with 1 equivalent of catecholate ligand (2,3-DHBA, 3,4-DHBA, 2,3,4-THBA or CafA) and then 2 equivalents of either bipy or phen. The complexes were characterised in full including by X-ray crystallography, which established that the catecholate ligands coordinate the Ga(III) centres in a bidentate manner the two deprotonated hydroxy groups. All Ga(III) complexes exhibited good antibacterial activity against the Gram-negative pathogenic bacteria , and .

and Display Differential Proteomic Responses to the Silver(I) Compound, SBC3.

The urgent need to combat antibiotic resistance and develop novel antimicrobial therapies has triggered studies on novel metal-based formulations. -heterocyclic carbene (NHC) complexes coordinate transition metals to generate a broad range of anticancer and/or antimicrobial agents, with ongoing efforts being made to enhance the lipophilicity and drug stability. The lead silver(I) acetate complex, 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*) (SBC3), has previously demonstrated promising growth and biofilm-inhibiting properties.

Design, Synthesis and Mechanistic Studies of Novel Isatin-Pyrazole Hydrazone Conjugates as Selective and Potent Bacterial MetAP Inhibitors.

Methionine aminopeptidases (MetAPs) are attractive drug targets due to their essential role in eukaryotes as well as prokaryotic cells. In this study, biochemical assays were performed on newly synthesized Isatin-pyrazole hydrazones () to identify potent and selective bacterial MetAP inhibitors. Compound inhibited prokaryotic MetAP, i.

Exposure of Candida parapsilosis to the silver(I) compound SBC3 induces alterations in the proteome and reduced virulence.

The antimicrobial properties of silver have been exploited for many centuries and continue to gain interest in the fight against antimicrobial drug resistance. The broad-spectrum activity and low toxicity of silver have led to its incorporation into a wide range of novel antimicrobial agents, including N-heterocyclic carbene (NHC) complexes. The antimicrobial activity and in vivo efficacy of the NHC silver(I) acetate complex SBC3, derived from 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*), have previously been demonstrated, although the mode(s) of action of SBC3 remains to be fully elucidated.

In Vivo Activity of Metal Complexes Containing 1,10-Phenanthroline and 3,6,9-Trioxaundecanedioate Ligands against Infection in Larvae.

Drug-resistant 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 from CF patients in vitro.

: The Versatile Host for Drug Discovery, In Vivo Toxicity Testing and Characterising Host-Pathogen Interactions.

Larvae of the greater wax moth, , are a convenient in vivo model for assessing the activity and toxicity of antimicrobial agents and for studying the immune response to pathogens and provide results similar to those from mammals. larvae are now widely used in academia and industry and their use can assist in the identification and evaluation of novel antimicrobial agents. larvae are inexpensive to purchase and house, easy to inoculate, generate results within 24-48 h and their use is not restricted by legal or ethical considerations.

Continuous flow synthesis and antimicrobial evaluation of NHC* silver carboxylate derivatives of SBC3 in vitro and in vivo.

N-heterocyclic silver carbene compounds have been extensively studied and shown to be active agents against a host of pathogenic bacteria and fungi. By incorporating hypothesized virulence targeting substituents into NHC-silver systems via salt metathesis, an atom-efficient complexation process can be used to develop new complexes to target the passive and active systems of a microbial cell. The incorporation of fatty acids and an FtsZ inhibitor have been achieved, and creation of both the intermediate salt and subsequent silver complex has been streamlined into a continuous flow process.

Quantitative proteomic reveals gallium maltolate induces an iron-limited stress response and reduced quorum-sensing in Pseudomonas aeruginosa.

Gallium-based drugs have been repurposed as antibacterial therapeutic candidates and have shown significant potential as an alternative treatment option against drug resistant pathogens. The activity of gallium (Ga) is a result of its chemical similarity to ferric iron (Fe) and substitution into iron-dependent pathways. Ga is redox inactive in typical physiological environments and therefore perturbs iron metabolism vital for bacterial growth.

UtilisingGalleria mellonella larvae for studying in vivo activity of conventional and novel antimicrobial agents.

The immune response of insects displays many structural and functional similarities to the innate immune response of mammals. As a result of these conserved features, insects may be used for evaluating microbial virulence or for testing the in vivo efficacy and toxicity of antimicrobial compounds and results show strong similarities to those from mammals. Galleria mellonella larvae are widely used in this capacity and have the advantage of being easy to use, inexpensive to purchase and house, and being free from the ethical and legal restrictions that relate to the use of mammals in these tests.