Porous isoreticular non-metal organic frameworks.

Metal-organic frameworks (MOFs) are useful synthetic materials that are built by the programmed assembly of metal nodes and organic linkers1. The success of MOFs results from the isoreticular principle2, which allows families of structurally analogous frameworks to be built in a predictable way. This relies on directional coordinate covalent bonding to define the framework geometry. However, isoreticular strategies do not translate to other common crystalline solids, such as organic salts3-5, in which the intermolecular ionic bonding is less directional. Here we show that chemical knowledge can be combined with computational crystal-structure prediction6 (CSP) to design porous organic ammonium halide salts that contain no metals. The nodes in these salt frameworks are tightly packed ionic clusters that direct the materials to crystallize in specific ways, as demonstrated by the presence of well-defined spikes of low-energy, low-density isoreticular structures on the predicted lattice energy landscapes7,8. These energy landscapes allow us to select combinations of cations and anions that will form thermodynamically stable, porous salt frameworks with channel sizes, functionalities and geometries that can be predicted a priori. Some of these porous salts adsorb molecular guests such as iodine in quantities that exceed those of most MOFs, and this could be useful for applications such as radio-iodine capture9-12. More generally, the synthesis of these salts is scalable, involving simple acid-base neutralization, and the strategy makes it possible to create a family of non-metal organic frameworks that combine high ionic charge density with permanent porosity.

The Lung Microbiome in COPD and Lung Cancer: Exploring the Potential of Metal-Based Drugs.

Chronic obstructive pulmonary disease (COPD) and lung cancer 17 are two of the most prevalent and debilitating respiratory diseases worldwide, both associated with high morbidity and mortality rates. As major global health concerns, they impose a substantial burden on patients, healthcare systems, and society at large. Despite their distinct aetiologies, lung cancer and COPD share common risk factors, clinical features, and pathological pathways, which have spurred increasing research interest in their co-occurrence. One area of particular interest is the role of the lung microbiome in the development and progression of these diseases, including the transition from COPD to lung cancer. Exploring novel therapeutic strategies, such as metal-based drugs, offers a potential avenue for targeting the microbiome in these diseases to improve patient outcomes. This review aims to provide an overview of the current understanding of the lung microbiome, with a particular emphasis on COPD and lung cancer, and to discuss the potential of metal-based drugs as a therapeutic strategy for these conditions, specifically concerning targeting the microbiome.

Controlling the Crystallisation and Hydration State of Crystalline Porous Organic Salts.

Crystalline porous organic salts (CPOS) are a subclass of molecular crystals. The low solubility of CPOS and their building blocks limits the choice of crystallisation solvents to water or polar alcohols, hindering the isolation, scale-up, and scope of the porous material. In this work, high throughput screening was used to expand the solvent scope, resulting in the identification of a new porous salt, CPOS-7, formed from tetrakis(4-sulfophenyl)methane (TSPM) and tetrakis(4-aminophenyl)methane (TAPM). CPOS-7 does not form with standard solvents for CPOS, rather a hydrated phase (Hydrate2920) previously reported is isolated. Initial attempts to translate the crystallisation to batch led to challenges with loss of crystallinity and Hydrate2920 forming favorably in the presence of excess water. Using acetic acid as a dehydrating agent hindered formation of Hydrate2920 and furthermore allowed for direct conversion to CPOS-7. To allow for direct formation of CPOS-7 in high crystallinity flow chemistry was used for the first time to circumvent the issues found in batch. CPOS-7 and Hydrate2920 were shown to have promise for water and CO2 capture, with CPOS-7 having a CO2 uptake of 4.3 mmol/g at 195 K, making it one of the most porous CPOS reported to date.

Antibacterial activity of metal-phenanthroline complexes against multidrug-resistant Irish clinical isolates: a whole genome sequencing approach.

Antimicrobial resistance (AMR) is one of the serious global health challenges of our time. There is now an urgent need to develop novel therapeutic agents that can overcome AMR, preferably through alternative mechanistic pathways from conventional treatments. The antibacterial activity of metal complexes (metal = Cu(II), Mn(II), and Ag(I)) incorporating 1,10-phenanthroline (phen) and various dianionic dicarboxylate ligands, along with their simple metal salt and dicarboxylic acid precursors, against common AMR pathogens were investigated. Overall, the highest level of antibacterial activity was evident in compounds that incorporate the phen ligand compared to the activities of their simple salt and dicarboxylic acid precursors. The chelates incorporating both phen and the dianion of 3,6,9-trioxaundecanedioic acid (tdda) were the most effective, and the activity varied depending on the metal centre. Whole-genome sequencing (WGS) was carried out on the reference Pseudomonas aeruginosa strain, PAO1. This strain was exposed to sub-lethal doses of lead metal-tdda-phen complexes to form mutants with induced resistance properties with the aim of elucidating their mechanism of action. Various mutations were detected in the mutant P. aeruginosa genome, causing amino acid changes to proteins involved in cellular respiration, the polyamine biosynthetic pathway, and virulence mechanisms. This study provides insights into acquired resistance mechanisms of pathogenic organisms exposed to Cu(II), Mn(II), and Ag(I) complexes incorporating phen with tdda and warrants further development of these potential complexes as alternative clinical therapeutic drugs to treat AMR infections.

Targeted design of porous materials without strong, directional interactions.

A porous molecular crystal (TSCl) was found to crystallise from dichloromethane and water during the synthesis of tetrakis(4-sulfophenylmethane). Crystal structure prediction (CSP) rationalises the driving force behind the formation of this porous TSCl phase and the intermolecular interactions that direct its formation. Gas sorption analysis showed that TSCl is permanently porous with selective adsorption of CO2 over N2, H2 and CH4 and a maximum CO2 uptake of 74 cm3 g-1 at 195 K. Calculations revealed that TSCl assembles via a combination of weak hydrogen bonds and strong dispersion interactions. This illustrates that CSP can underpin approaches to crystal engineering that do not involve more intuitive directional interactions, such as hydrogen bonding.

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

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.

The Antibacterial Drug Candidate SBC3 is a Potent Inhibitor of Bacterial Thioredoxin Reductase.

Antibiotic resistance is a growing problem for public health and associated with increasing economic costs and mortality rates. Silver and silver-related compounds have been used for centuries due to their antimicrobial properties. In this work, we show that 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene silver(I) acetate/NHC*-Ag-OAc (SBC3) is a reversible, high affinity inhibitor of E. coli thioredoxin reductase (TrxR; Ki =10.8±1.2 nM). Minimal inhibition concentration (MIC) tests with different E. coli and P. aeruginosa strains demonstrated that SBC3 can efficiently inhibit bacterial cell growth, especially in combination with established antibiotics like gentamicin. Our results show that SBC3 is a promising antibiotic drug candidate targeting bacterial TrxR.

The Antibacterial and Anti-biofilm Activity of Metal Complexes Incorporating 3,6,9-Trioxaundecanedioate and 1,10-Phenanthroline Ligands in Clinical Isolates of Pseudomonas Aeruginosa from Irish Cystic Fibrosis Patients.

Chronic infections of Pseudomonas aeruginosa in the lungs of cystic fibrosis (CF) patients are problematic in Ireland where inherited CF is prevalent. The bacteria's capacity to form a biofilm in its pathogenesis is highly virulent and leads to decreased susceptibility to most antibiotic treatments. Herein, we present the activity profiles of the Cu(II), Mn(II) and Ag(I) tdda-phen chelate complexes {[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; phen = 1,10-phenanthroline) towards clinical isolates of P. aeruginosa derived from Irish CF patients in comparison to two reference laboratory strains (ATCC 27853 and PAO1). The effects of the metal-tdda-phen complexes and gentamicin on planktonic growth, biofilm formation (pre-treatment) and mature biofilm (post-treatment) alone and in combination were investigated. The effects of the metal-tdda-phen complexes on the individual biofilm components; exopolysaccharide, extracellular DNA (eDNA), pyocyanin and pyoverdine are also presented. All three metal-tdda-phen complexes showed comparable and often superior activity to gentamicin in the CF strains, compared to their activities in the laboratory strains, with respect to both biofilm formation and established biofilms. Combination studies presented synergistic activity between all three complexes and gentamicin, particularly for the post-treatment of established mature biofilms, and was supported by the reduction of the individual biofilm components examined.

Disarming Pseudomonas aeruginosa Virulence by the Inhibitory Action of 1,10-Phenanthroline-5,6-Dione-Based Compounds: Elastase B (LasB) as a Chemotherapeutic Target.

Elastase B (lasB) is a multifunctional metalloenzyme secreted by the gram-negative pathogen Pseudomonas aeruginosa, and this enzyme orchestrates several physiopathological events during bacteria-host interplays. LasB is considered to be a potential target for the development of an innovative chemotherapeutic approach, especially against multidrug-resistant strains. Recently, our group showed that 1,10-phenanthroline-5,6-dione (phendione), [Ag(phendione)2]ClO4 (Ag-phendione) and [Cu(phendione)3](ClO4)2.4H2O (Cu-phendione) had anti-P. aeruginosa action against both planktonic- and biofilm-growing cells. In the present work, we have evaluated the effects of these compounds on the (i) interaction with the lasB active site using in silico approaches, (ii) lasB proteolytic activity by using a specific fluorogenic peptide substrate, (iii) lasB gene expression by real time-polymerase chain reaction, (iv) lasB protein secretion by immunoblotting, (v) ability to block the damages induced by lasB on a monolayer of lung epithelial cells, and (vi) survivability of Galleria mellonella larvae after being challenged with purified lasB and lasB-rich bacterial secretions. Molecular docking analyses revealed that phendione and its Ag+ and Cu2+ complexes were able to interact with the amino acids forming the active site of lasB, particularly Cu-phendione which exhibited the most favorable interaction energy parameters. Additionally, the test compounds were effective inhibitors of lasB activity, blocking the in vitro cleavage of the peptide substrate, aminobenzyl-Ala-Gly-Leu-Ala-p-nitrobenzylamide, with Cu-phendione having the best inhibitory action (K i = 90 nM). Treating living bacteria with a sub-inhibitory concentration (½ × MIC value) of the test compounds caused a significant reduction in the expression of the lasB gene as well as its mature protein production/secretion. Further, Ag-phendione and Cu-phendione offered protective action for lung epithelial cells, reducing the A549 monolayer damage by approximately 32 and 42%, respectively. Interestingly, Cu-phendione mitigated the toxic effect of both purified lasB molecules and lasB-containing bacterial secretions in the in vivo model, increasing the survival time of G. mellonella larvae. Collectively, these data reinforce the concept of lasB being a veritable therapeutic target and phendione-based compounds (mainly Cu-phendione) being prospective anti-virulence drugs against P. aeruginosa.