Metal-Based Drugs for Lung Microbiome in COPD: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Megan O'Shaughnessy.

The concept of the lung microbiome has been radically altered with the understanding that the human lung hosts a complex ecosystem comprised of bacteria, fungi, and viruses, which actively participate in maintaining respiratory health by contributing to immune modulation, pathogen displacement, and metabolic contributions. The composition of the respiratory microbiome is transient and determined by continuous microbial immigration (through microaspiration, inhalation, and direct mucosal spread), elimination (by the immune system and mucociliary clearance), and replication. The notion of a healthy lung microbiome refers to a state in which a multitude of beneficial microorganisms coexist in harmony, promoting an immune environment that is neither too reactive nor too lax, providing robustness against invading pathogens, and supporting the crucial function of the lungs. 

  • lung microbiome
  • chronic obstructive pulmonary disease
  • lung cancer
  • metal-based drugs
  • phenanthroline

1. The Lung Microbiome in Lung Disease

Numerous studies have distinguished the lung microbiome in human health and disease, in which a shift of the microbiome is associated with diseases and key clinical parameters, such as severity, exacerbation, phenotype, endotype, inflammation, and mortality [57,59,60,61][1][2][3][4]. Dysbiosis, characterised by a decrease in microbial diversity and a shift in community composition, is observed in various respiratory disorders, including asthma, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), tuberculosis, chronic obstructive pulmonary disease (COPD), and lung cancer [62,63,64,65,66,67][5][6][7][8][9][10]. Diversity is a measure of the evenness and richness of a microbial community, which can be measured within a biological sample (α-diversity) or between samples (β-diversity) [68,69][11][12]. Lower bacterial diversity has been linked to disease progression, although it is unknown whether microbial dysbiosis is a cause or effect of the disease [2,7,70][13][14][15]. Dysbiosis may have a causative role in lung diseases by upregulating inflammatory signals (such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Ras, IL-17, and phosphoinositide 3-kinase (PI3K)) [67,71,72,73,74][10][16][17][18][19] or by suppressing the production of TNF and interferon-gamma (IFNγ) in response to pathogen presence in the lower respiratory tract [58,75][20][21]. The following sections will focus specifically on the lung microbiome in COPD and lung cancer.

1.1. Chronic Obstructive Pulmonary Disease (COPD)

COPD is a chronic inflammatory lung condition characterised by persistent respiratory symptoms and progressive airflow restriction. Predominantly triggered by long-term exposure to harmful pollutants, such as cigarette smoke and environmental toxins, it clinically presents with dyspnoea, chronic cough, sputum production, and wheezing [76,77][22][23]. The disease comprises two primary phenotypes: chronic bronchitis, hallmarked by a chronic productive cough, and emphysema, typified by alveolar wall destruction over time. COPD, as a progressive and potentially fatal condition, can significantly deteriorate quality of life due to recurrent exacerbations and a decline in pulmonary function [77,78,79][23][24][25]. Although there is no definitive cure at present, the management of symptoms and decelerating disease progression are pivotal. Recent research has begun to shed light on the role of the lung microbiome in the pathogenesis and progression of COPD, offering a new perspective on this debilitating disease [80,81,82][26][27][28]. Gram-negative pathogenic bacteria tied to COPD (Haemophilus spp., Moraxella, Pseudomonas) possess a notably higher potential to stimulate an immune response compared to Gram-negative commensal bacteria (Prevotella spp.) [83][29]. Poor oral hygiene has been identified as a risk factor for inflammatory lung conditions through microaspiration of oral commensals, such as Veillonella and Prevotella, which have been associated with increased TH17 lymphocytes within the lung [71,84][16][30]. Several studies have reported the composition of the airway microbiome in COPD and found a shift in microbiome diversity with a decrease in Bacillota (Firmicutes) and Bacteroidota and an increase in Pseudomonadota, particularly the genus Haemophilus, which positively correlated with IL-8 present in sputum [8,80,85,86,87,88][26][31][32][33][34][35]. This shift in the microbiome composition, particularly the elevation in Pseudomonadota, has been associated with greater emphysema, and increased immune cell infiltration leading to chronic inflammation, airway remodelling, and exacerbations [88,89,90,91,92][35][36][37][38][39]. Exacerbations, defined as acute worsening of respiratory symptoms, significantly contribute to the morbidity and mortality associated with COPD. These episodes are often triggered by bacterial or viral infections and treated with antibiotics and corticosteroids, critical elements in the standard therapeutic approach [93][40]. Antibiotic-mediated perturbation of the gut microbiome has been widely reported to be associated with numerous infectious and autoimmune diseases of the gastrointestinal tract [94,95,96,97][41][42][43][44]. Although less extensively studied, antibiotic use has been reported to cause alterations in the lung microbiome, which can negatively impact the ecological balance of microbial communities within the lung and potentially escalate disease progression and exacerbation severity [56,98][45][46]. Moreover, dysbiosis may potentiate bacterial resistance, creating challenges for future antimicrobial treatment [99,100][47][48]. Thus, while antibiotics and corticosteroids are essential for managing COPD exacerbations, their impact on the lung microbiome warrants careful consideration within therapeutic strategies [101][49].
The lung microbiome in COPD has been found to be significantly associated with bacterial biomass, lymphocyte proportion, TH17 immune response, exacerbation frequency, and resistance to antimicrobial therapy [102][50]. Initial investigations into the microbiome of patients with stable COPD have demonstrated a significant correlation between the presence of pathogenic bacteria, such as Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, Staphylococcus aureus, Pseudomonas aeruginosa, and Enterobacterales. As COPD progresses, chronic inflammation impairs the innate immune response within the lung, which in turn creates a favourable environment for an increase in bacterial burden. Numerous studies have shown that in moderate to severe COPD (Global Initiative for COPD (GOLD) 2–4), there is an enrichment of Gammaproteobacteria (Haemophilus and Moraxella spp.) in bronchiole lavage and lung tissue samples [80,103,104][26][51][52]. Erb-Downward et al. [80][26] found that the microbiomes of patients with moderate or severe COPD had lower bacterial diversity scores than healthy smokers and non-smokers. They identified a core COPD lung microbiome that included Pseudomonas, Streptococcus, Prevotella, Fusobacterium, Haemophilus, Veillonella, and Porphyromonas [80][26]. Interestingly, in patients with very advanced COPD, there were significant differences in the microbiomes at adjacent lung sites, suggesting heterogeneity within the individual lung microbiome. In a similar vein, Sze et al. [105][53] evaluated the microbiomes in lung tissues taken from patients with severe COPD (GOLD 4) at the time of lung transplantation and found an increase in bacterial diversity in patients with severe COPD compared to non-smokers, smokers, and patients with CF, with a notable increase in the phylum Bacillota (Firmicutes), specifically Lactobacillus [105][53]. These findings highlight the dynamic nature of the lung microbiome in COPD patients and the differences across sample types. In a longitudinal observational study analysing the microbiome of sputum of clinically stable COPD patients, reduced microbiome diversity was observed associated with Pseudomonadota (predominantly Haemophilus) dominance, which was associated with neutrophil-associated protein profiles and an increased risk of mortality [89][36]. In a recent cohort study, longitudinal sputum samples were taken from COPD patients during acute exacerbation (AECOPD), which found significant positive correlations between the abundance of Pseudomonas and TNF, the abundance of Klebsiella, and the percentage of eosinophils. Furthermore, the study identified four clusters of COPD based on the respiratory microbiome, with the AECOPD-related cluster characterised by the enrichment of Pseudomonas and Haemophilus and a high level of TNF [88][35]. Therefore, these patients might benefit from targeted antibacterial agents, which may aid in alleviating inflammation. In contrast, patients with a diverse microbiome profile, including Veillonella and Prevotella, exhibited a more dynamic microbiome over time and showed elevations of IL-17A within sputum and serum [106][54]. It was observed that these patients had greater microbiome shifts during exacerbations and, therefore, would profit from an anti-inflammatory therapeutic strategy. This growing body of evidence underscores the intricate relationship between the lung microbiome and COPD, shedding light on the potential of microbiota-targeted interventions to improve the long-term prognosis of COPD. However, a comprehensive understanding of these relationships warrants further in-depth investigations, including longitudinal studies to track microbiome changes over time and interventional studies to test the causality of observed associations.

1.2. Lung Cancer

Lung cancer, a heterogeneous group of malignancies arising in the lung parenchyma or bronchi, is the leading cause of cancer-related deaths globally [107][55]. The disease is classified into non-small cell lung cancer (NSCLC), which constitutes about 85% of cases, and small cell lung cancer (SCLC), which represents the remaining 15%. The three main subtypes of NSCLC are adenocarcinoma (40%), squamous cell carcinoma (25–30%), and large cell carcinoma (5–10%). Lung cancer is typically asymptomatic in the early stages, with clinical manifestations such as persistent cough, chest pain, and haemoptysis emerging as the disease progresses [108,109,110][56][57][58]. The predominant contributors to lung cancer include exposure to tobacco smoke, environmental toxins, carcinogens, persistent airway inflammation instigated by pathogenic infections, as well as fibrosis and scarring resulting from co-existing lung diseases [29,111][59][60]. Despite advancements in therapeutic interventions, lung cancer continues to be a primary cause of death related to cancer worldwide due to its late-stage diagnosis and high recurrence rates, even in those with early-stage disease. Comprehensive strategies for early detection and treatment are crucial to reducing the global burden of the disease.
The intricate relationship between the lung microbiome and lung cancer has begun to be elucidated. Research has shown associations between specific bacterial phyla, family, genera, and species and the progression of lung cancer. Among these are Actinomycetota, Bacteroidota, Pseudomonadota, Bacillota (Firmicutes) [112][61], Capnocytophaga, Neisseria, and Selenomonas [113][62], Thermus, Legionella, Megasphaera, Veillonella [114][63], Cyanobacteria [115][64], Acidovorax temporans [33][65] and Helicobacter pylori [116][66]. Dysbiosis of the microbiome is mainly manifested by the decrease in symbiotic bacteria and the increase in pathogenic bacteria, and then inducement of carcinogenesis at multiple levels, including metabolism alteration, inflammation, and altered immune response [117,118][67][68]. Several studies have pointed towards an increased abundance of certain genera, such as Veillonella, Streptococcus, and Prevotella, in lung cancer patients compared to healthy individuals, which have also been observed in patients with COPD [119,120][69][70]. For example, a study by Yu et al. [121][71] reported that the microbiota of lung tumour tissue showed significantly lower α-diversity compared to non-malignant lung tissue samples, with higher levels of Veillonella. Moreover, it was reported that bacterial composition correlated with cancer stage, with a higher abundance of Thurmus in advanced-stage (IIIB, IV) patients, and Legionella in patients with metastases [121][71]. Studies have also indicated an enrichment of Veillonella and Megasphaera in the bronchoalveolar lavage fluid (BALF) of patients diagnosed with NSCLC stages II-IV (72% adenocarcinoma and 28% squamous cell carcinoma), suggesting these genera could serve as biomarkers to predict disease progression [113][62]. Complementary findings by Huang et al. [122][72] support this observation in the bronchial washing fluid of patients with lung adenocarcinoma compared to those with squamous cell lung carcinoma. Gomes et al. [114][63] reported that lung cancer microbiota was enriched in Pseudomonadota and more diverse in squamous cell carcinoma than adenocarcinoma, particularly in males and heavier smokers, suggesting a potential link between these bacteria and the presence of other risk factors. Najafi et al. [123][73] found that the relative abundance of several bacterial taxa, including Actinomycetota phylum, Corynebacteriaceae, and Halomonadaceae families, and Corynebacterium, Lachnoanaerobaculum, and Halomonas genera, is significantly decreased in lung tumour tissues of lung cancer patients in comparison with matched tumour-adjacent normal tissues. The microbiota within the airway plays a distinct role in the onset and progression of lung cancer. Research has indicated that mice, either germ-free or treated with antibiotics, show considerable resistance against lung cancer development, even with Kras mutation and p53 loss [124][74]. Other studies have identified differences in the gut microbiota between patients with lung cancer and healthy controls, with an increased abundance of Enterococcus and decreased levels of the phylum Actinomycetota and genus Bifidobacterium [125][75]. The “gut-lung axis” is an emerging concept linking the state of the gut microbiota to respiratory health outcomes [126,127][76][77]. Simultaneously, it was observed that depleting the microbiota or inhibiting γδ T cells or their downstream effector molecules all effectively suppressed the growth of lung adenocarcinoma in a genetically engineered mouse model driven by an activating point mutation of Kras and loss of p53 [128][78]. The role of the resident microbiome in the progression of lung cancer was further examined in a nested case control study encompassing 4336 lung cancer subjects and 10,000 matched controls aged 40–84 years [129][79]. The study sought to establish any correlation between antibiotic usage and the risk of lung cancer. Remarkably, subjects who received 10 or more antibiotic courses presented a relative lung cancer risk of 2.52 (95% CI, 2.25–2.83) compared with controls who had not received antibiotics. The elevated relative risk could potentially be attributed to the inflammatory conditions induced by frequent infections and consequent alterations in the lung microbiomes among those administered antibiotics [129][79].
The proposed theory is that dysbiosis or microbial imbalance might propel carcinogenesis through three channels: (i) disruption of immune equilibrium, (ii) chronic inflammation instigation, and (iii) activation of cancer-causing pathways [130,131,132,133,134][80][81][82][83][84]. Firstly, dysbiosis has the potential to disrupt the lung immune system’s fundamental stimulation, and depletion of microbial diversity impairs the initial activation of antigen-presenting cells, thereby inhibiting their response to tumour antigens [2][13]. Conversely, bacterial overgrowth can lead to an overstimulation of the immune system and unchecked proliferation of IL-17-producing CD4+ helper T (TH17) cells, mediators in lung tumorigenesis [135][85]. Secondly, dysbiosis incites chronic inflammation via the release of DNA-damaging metabolites and genotoxins from commensal organisms. Inflammatory cells activated by dysbiosis can also release reactive oxygen (ROS) and nitrogen (RNS) species, promoting carcinogenesis and angiogenesis [136,137][86][87]. Lastly, several studies have highlighted that some species within the microbiota can directly stimulate cancer-causing pathways. For instance, Apopa et al. [115][64] demonstrated an increase in PARP1 in NSCLC tissues in the presence of the cyanobacteria toxin microcystin. Likewise, research by Tsay et al. [67][10] connected Streptococcus and Veillonella to the stimulation of the PI3K and extracellular signal-regulated protein kinase (ERK) pathways involved in the disease. Ochoa et al. [138][88] found that exposure of the airway to smoke particulates and nontypeable H. influenzae (NTHi) promoted lung cancer cell proliferation by release of IL-6 and TNF, which further activated the STAT3 and NF-κB pathways in the airway epithelium. Interestingly, it was demonstrated that IL-6 blockade significantly inhibited lung cancer promotion, tumour cell-intrinsic STAT3 activation, tumour cell proliferation, and angiogenesis markers [139][89]. As previously mentioned, TH17 cell-mediated inflammation has been identified as playing a critical role in lung tumorigenesis [140][90]. Jungnickel et al. [73][18] indicated that the epithelial cytokine IL-17C mediates the tumour-promoting effect of bacteria, such as NTHi, through neutrophilic inflammation. There has been growing awareness of the importance of NTHi in the pathophysiology of COPD, and COPD-like airway inflammation induced by NTHi provides a tumour microenvironment that favours cancer promotion and progression [141,142,143][91][92][93]. Thus, NTHi may act as a bridge between COPD and lung cancer. Despite these encouraging findings associating specific microbes with carcinogenesis, distinguishing between microbes genuinely inducing cancer-causing pathways and those opportunistically colonising the tumour microenvironment remains a challenge. However, given the impact of dysregulated lung microbiomes on diseases such as COPD and lung cancer, the exploration of innovative therapeutics is warranted. Metal-based drugs offer a promising avenue with their potential to modulate the microbiome, alleviate inflammation, and directly target malignant cells.

2. Metal Drugs as Microbiome Modulators

The current antimicrobial clinical pipeline is inadequate to treat mounting infections caused by multidrug-resistant pathogens [180][94]. Of the 12 new antibacterial agents approved for clinical use since 2017, the WHO reported that only one compound, cefiderocol, meets their innovation criteria (absence of known cross-resistance, new target, a new mode of action, or new class) that also has activity against all three critical priority pathogens [181][95]. Cefiderocol is a siderophore-conjugated cephalosporin that promotes the formation of chelated complexes with ferric iron and facilitates siderophore-like transport across the outer membrane of Gram-negative bacteria using iron transport systems accumulating in the periplasmic space [182,183][96][97]. This has highlighted the essential need to investigate ‘non-traditional’ approaches to antibacterial therapy that explore different avenues compared to ‘traditional’ organic molecules that target pathogens through already established targets [184,185][98][99]. These agents can prevent or treat bacteria through several modes of action, including directly or indirectly inhibiting growth, dampening virulence, truncating, or removing biofilm, alleviating resistance, restoring the natural microbiome, or boosting the immune system to clear or manage infections [184,186,187][98][100][101]. Metal-bearing drugs can adopt a range of coordination geometries and redox states, allowing for more significant chemical variations when compared with purely organic antibiotics, with different and potentially multi-modal mechanisms of action [40,179,188][102][103][104]. For instance, a recent study by the Community for Open Antimicrobial Drug Discovery (CO-ADD), a global free open-access screening initiative, discussed metal complexes’ enhanced activity profile [189][105]. The group evaluated 906 individual metal compounds within their database, from d-block elements, against critical ESKAPE bacteria and fungi, and found an impressive success rate of the metal compounds (9.9%) in comparison to solely organic molecules (0.87%). From this panel of metal complexes, 88 demonstrated activity (minimum inhibitory concentration (MIC) ≤ 16 µg/mL or 10 µM) against one of their tested strains (58 against fungi and 30 against bacteria) while also being tolerated by mammalian cells (CC50 > 32 µg/mL or >20 µM against human embryonic kidney cell line) and not demonstrating haemolytic activity (HC10 > 32 µg/mL or >20 µM). Only 14 of these metal complexes showed activity (MIC ≤ 32 µg/mL) against Gram-negative bacteria, including pathogenic bacteria tied to COPD and lung cancer [83,114][29][63]. Overall, the group emphasised the potential therapeutic capabilities of metal compounds due to the extent of possible modes of action, with broader coverage of three-dimensional chemical space than their organic counterparts [189][105]. The diverse antimicrobial mechanisms of metal-based drugs offer a promising avenue of exploration for the treatment of respiratory diseases, where dysbiosis plays a significant role, including COPD and lung cancer. The subsequent sections will focus on notable discoveries of metal-based compounds that have been studied as antimicrobial agents and exhibit the characteristics of microbiome modulators. However, it is in no way exhaustive. The coordination of metals to organic ligands such as 1,10-phenanthroline (phen) will also be discussed, as metal-phen complexes are emerging as tangible alternatives to the traditional antibiotic, with some studies reporting targeted inhibition and suppression of virulence as opposed to indiscriminate toxicity [190][106]. This presents an exciting new frontier for future research and therapeutic strategies for these prevalent and challenging diseases.

2.1. Bismuth (Bi)

Bi compounds have been utilised for many years to treat gastrointestinal disorders, including H. pylori infections, which are commonly associated with gastritis, and peptic ulcer disease, and are a well-established risk factor associated with the development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma and gastric cancer [191,192,193][107][108][109]. In fact, due to the acidic environment of the stomach, it was also historically thought to be a sterile organ until the landmark discovery of H. pylori infection and its association with gastric disease [194][110]. H. pylori is a Gram-negative, microaerophilic bacteria which colonises the gastric mucosa of over half the world’s population, making it one of the most widespread bacterial infections [195][111]. Although 80% of H. pylori-infected individuals remain asymptomatic, some develop chronic gastritis, peptic ulcers, and eventually gastric cancer. Gastric cancer is the fourth leading cause of cancer-related deaths globally, and H. pylori infection accounts for nearly 90% of all non-cardia gastric adenocarcinomas [196][112]. Eradication of H. pylori infection can reduce the risk of gastric cancer development, especially if treated early before the onset of precancerous lesions [197][113]. The standard treatment for H. pylori infection is a combination of proton pump inhibitors (PPIs) and antibiotics (clarithromycin, amoxicillin, or metronidazole). The emergence of antibiotic resistance has led to a decline in the effectiveness of these regimens [198][114]. However, the synergistic effect between Bi salts and antibiotics has been observed, making Bi-containing quadruple therapy a recommended first-line treatment in areas with a high prevalence of antibiotic resistance [199][115]. Bi has a multi-targeted mode of antimicrobial activity by disrupting the bacterial cell envelope, interfering with enzyme function, inhibiting bacterial protein synthesis, and disrupting nickel homeostasis [40,200][102][116]. Nickel is essential for the survival and pathogenesis of H. pylori, as it regulates nickel acquisition, storage, delivery, and efflux via the synthesis of various metalloproteins/chaperones [201][117]. Bi drugs can interfere with nickel homeostasis by binding to nickel-associated proteins that play a critical role in urease and [Ni,Fe]-hydrogenase maturation, leading to the inhibition of enzyme activity. It has been widely reported that in addition to antimicrobial activity, Bi compounds exhibit anti-inflammatory and gastroprotective properties, which contribute to their effectiveness in treating these conditions and highlight their potential as a microbiome modulator [202,203][118][119].

2.2. Gold (Au)

Auranofin, an Au-based compound initially developed and approved for rheumatoid arthritis, has recently been recognised as a promising microbiome modulator. The antimicrobial potency of auranofin has been demonstrated against a broad spectrum of pathogenic bacteria, including antibiotic-resistant strains, such as Clostridioides difficile, M. tuberculosis, methicillin-resistant S. aureus (MRSA), and vancomycin-resistant Enterococcus (VRE), both in vitro and in vivo [49,204,205,206][120][121][122][123]. The modus operandi of its antimicrobial action is its ability to disrupt the redox balance within bacteria by inhibiting the TrxR enzyme, an essential component of their antioxidant defence mechanism [205][122]. Additionally, auranofin has been shown to have anti-virulence properties, reducing the production of key virulence factors, including proteases, lipase, and haemagglutinin [207][124]. Interestingly, auranofin’s influence on the microbiome extends beyond its antimicrobial properties. The inherent anti-inflammatory properties of the drug also hold implications for microbiome modulation. It achieves this by curtailing the expression of pro-inflammatory cytokine IL-6 via the inhibition of the NF-κB-IL-6-STAT3 signalling cascade, a critical pathway involved in the pathogenesis of various inflammatory diseases [208][125]. By mitigating local inflammation, auranofin maintains the integrity of the host barrier, thereby fostering a more conducive environment for beneficial bacteria. For instance, in murine models, auranofin treatment led to decreased inflammation and a shift towards a more balanced microbiota, characterised by an increase in anti-inflammatory bacterial strains such as Faecalibacterium prausnitzii [209,210,211][126][127][128]. Thus, auranofin presents a dual action microbiome modulator, harnessing both antimicrobial and anti-inflammatory capabilities. This novel mechanism of action offers a promising avenue for therapeutic intervention in conditions characterised by microbial imbalance, although further research is warranted to fully elucidate its potential clinical utility. Moreover, recent studies have focused on auranofins’ potential asan anticancer agent, showing its efficacy against various cancers, including lung cancer (IC50 < 2 μM, for A549) [169[129][130][131][132],212,213,214], while also enhancing Ibrutinib (tyrosine kinase inhibitor) activity in EGFR-mutant lung adenocarcinoma [215][133]. Mimicking its antimicrobial mechanism of action, auranofin is a selective inhibitor of TrxR, triggering increased production of ROS and activating the p38 mitotic activated protein kinase (p38 MAPK) [216][134]. It has also been reported that auranofin can inhibit proteasome-associated deubiquitinases (DUB), deregulating the ubiquitin-proteasome system (UPS) [217][135]. The proven effectiveness of auranofin in cancer management has sparked interest among pharmaceutical chemists in exploring other Au(I) complexes for their potential therapeutic roles. The future of Au-based drugs, thus, presents an intriguing avenue for cancer treatment, in particular cancer that arises from microbiome dysbiosis.

2.3. Silver (Ag)

Silver has long been known for its potent antimicrobial properties, both historically and in modern times. A variety of medical products containing silver are available, such as bandages, ointments, and catheters in the form of nanocrystalline silver (including silver nanoparticles and colloidal silver), silver nitrate, and silver sulfadiazine (a complex formed with the antibiotic sulfadiazine) [218][136]. Ag(I) compounds have well-documented multi-modal properties that exhibit broad-spectrum activity against a wide range of bacterial species, including Gram-positive and Gram-negative bacteria, as well as fungi and viruses [219,220][137][138]. The toxicity of Ag(I) compounds primarily stems from the release of ions that interact with the cell envelope and destabilise the membrane [221[139][140],222], coupled with nucleic acids and proteins disrupting replication and synthesis [223][141] and inhibiting metabolic pathways [199,224][115][142]. Although Ag(I) is generally not regarded as redox-active, the generation of ROS is also attributed to its antibacterial activity [35,48,219][137][143][144]. However, it is thought that the production of ROS indirectly occurs through the perturbation of the respiratory electron transfer chain [225][145], Fenton chemistry following destabilisation of Fe-S clusters or displacement of Fe [226][146] and inhibition of anti-ROS defences by thiol–Ag bond formation [227][147]. Studies have also shown that Ag(I) often exhibits synergistic effects when combined with a range of antibiotics, such as β-lactams [228[148][149][150],229,230], aminoglycosides [48,230,231,232][144][150][151][152] and fluoroquinolones [229[149][150],230], and tetracyclines [48][144], against both planktonic and biofilm forms. While the direct antimicrobial effects of Ag(I) are well documented, its role as a microbiome modulator has been an area of growing interest in recent years and has produced contradictory results thus far. An in vivo study evaluating changes in the populations of intestinal-microbiota and intestinal-mucosal gene expression in rats after oral administration of Ag nanoparticles (AgNP) (9, 18, and 36 mg/kg body weight/day) and silver acetate (100, 200, and 400 mg/kg body weight/day). The results indicate that exposure to AgNP prompted size- and dose-dependent changes to ileal mucosal microbial populations, as well as intestinal gene expression, and induced an apparent shift in the gut microbiota toward greater proportions of Gram-negative bacteria [233][153]. In contrast, another study found non-significant alterations in the Bacillota (Firmicutes) and Bacteroidota populations with no toxicological effects on rats that received AgNPs orally by gavage for 28 days [234][154]. Various studies have reported that the shape of AgNPs can influence their impact on gut microbiota. For example, cubic AgNPs have been shown to reduce the abundance of Christensenellaceae, Clostridium spp., Bacteroides uniformis, and Coprococcus eutectic [235][155], while spherical AgNPs decrease the presence of Oscillospira spp., Dehalobacterium spp., Peptococcaceae, Corynebacterium spp., and Aggregatibacter pneumotropica populations [236][156]. Ag(I) complexes have also been studied for their potential use as anticancer agents due to their unique properties and interaction with cellular components, such as DNA and proteins, leading to disruption of essential biological processes [237][157]. For example, Ag(I) complexes with N-heterocyclic carbene ligands have been studied for their anticancer activities against a range of cancer cell lines, including lung cancer [238][158].

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