Breaking Iron Homeostasis: Iron Capturing Nanocomposites for Combating Bacterial Biofilm.

Given the scarcity of novel antibiotics, the eradication of bacterial biofilm infections poses formidable challenges. Upon bacterial infection, the host restricts Fe ions, which are crucial for bacterial growth and maintenance. Having coevolved with the host, bacteria developed adaptive pathways like the hemin-uptake system to avoid iron deficiency. Inspired by this, we propose a novel strategy, termed iron nutritional immunity therapy (INIT), utilizing Ga-CT@P nanocomposites constructed with gallium, copper-doped tetrakis (4-carboxyphenyl) porphyrin (TCPP) metal-organic framework, and polyamine-amine polymer dots, to target bacterial iron intakes and starve them. Owing to the similarity between iron/hemin and gallium/TCPP, gallium-incorporated porphyrin potentially deceives bacteria into uptaking gallium ions and concurrently extracts iron ions from the surrounding bacteria milieu through the porphyrin ring. This strategy orchestrates a "give and take" approach for Ga3+/Fe3+ exchange. Simultaneously, polymer dots can impede bacterial iron metabolism and serve as real-time fluorescent iron-sensing probes to continuously monitor dynamic iron restriction status. INIT based on Ga-CT@P nanocomposites induced long-term iron starvation, which affected iron-sulfur cluster biogenesis and carbohydrate metabolism, ultimately facilitating biofilm eradication and tissue regeneration. Therefore, this study presents an innovative antibacterial strategy from a nutritional perspective that sheds light on refractory bacterial infection treatment and its future clinical application.

Synthesis, characterization and in vitro cytotoxicity of gallium(III)-dithiocarbamate complexes.

A library of homoleptic mononuclear Ga(III) complexes of the general formula [Ga(DTC)3], where DTC is an alicyclic or a linear dithiocarbamate chelator, is reported. The complexes were prepared in high yields starting from Ga(NO3)3·6H2O and fully characterized by elemental analysis and IR and NMR spectroscopy. Crystals of five of these complexes were obtained. The antitumor activity of the newly synthesized compounds against a panel of human cancer cell lines was evaluated. The chemical nature of the DTC does not have a marked impact on the structural features of the final compound. X-ray crystal structure analyses revealed that all these complexes have a trigonal prismatic geometry with three identical chelating DTCs coordinating the Ga(III) ion. It is noteworthy that in complex 22, [Ga(NHEt)3] (NHEt = N-ethyldithiocarbamate), the asymmetric unit is formed by two independent and structurally different molecules. Cellular studies showed that all the synthesized Ga-DTC complexes exhibit marked cytotoxic activity, even against human colon cancer cells that are less sensitive to cisplatin. Among the tested compounds, 6 ([Ga(CEPipDTC)3], CEPipDTC = (ethoxycarbonyl)-piperidinedithiocarbamate) and 21 ([Ga(Pr-13)3], PR13 = 4 and N-(2-ethoxy-2-oxoethyl)-N-methyldithiocarbamate) are very promising derivatives, but they have no selectivity towards cancer cells. Nevertheless, the obtained data provide a foundation for developing gallium-dithiocarbamate complexes as anticancer agents.

Boron deficiency decreased the root activity of Ga-exposed rice seedlings by reducing iron accumulation and increasing Ga in iron plaque.

Gallium (Ga) is an emerging chemical pollutant chiefly associated with high-tech industries. Boron (B) alleviates the negative effects of toxic elements on plant growth. Thereby, the effects of B fertilization on Ga toxicity in rice seedlings was studied to clarify the role of iron plaque in the distribution of Ga, Fe, and B in Ga-treated rice seedlings in the presence or absence of B. Gallium exposure significantly reduced the biomass of rice seedlings. Boron deficiency induced a significant change in the distribution of B in Ga-treated rice seedlings compared with "Ga+B" treatments. Accumulation of Ga in roots, dithionite-citrate-bicarbonate (DCB) extracts, and shoots showed a dose-dependent manner from both +B and -B rice seedlings. Boron nutrition levels affect the distribution of Fe in roots, DCB extracts, and shoots, in which DCB-extractable Fe was significantly decreased from "Ga-B" treatments compared with "Ga+B" treatments. Root activity was significantly decreased in both Ga-exposed rice seedlings; however, B-deficient seedlings showed a severe reduction than +B rice seedlings. These results reveal that Fe plaque might be a temporary sink for B accumulation when plants are grown with proper B, wherein the re-utilization of DCB-extractable B stored in Fe plaque is mandatory for plant growth under B deficiency. Correlation analysis revealed that B deficiency decreased the root activity of Ga-exposed rice seedlings by reducing DCB-extractable Fe and increasing DCB-extractable Ga in Fe plaque. This study enhances our understanding of how B nutritional levels affect Ga toxicity in rice plants.

New Stable Gallium(III) and Indium(III) Complexes with Thiosemicarbazone Ligands: A Biological Evaluation.

The aim of this work is to explore a new library of coordination compounds for medicinal applications. Gallium is known for its various applications in this field. Presently, indium is not particularly important in medicine, but it shares a lot of chemical traits with its above-mentioned lighter companion, gallium, and is also used in radio imaging. These metals are combined with thiosemicarbazones, ligating compounds increasingly known for their biological and pharmaceutical applications. In particular, the few ligands chosen to interact with these hard metal ions share the ideal affinity for a high charge density. Therefore, in this work we describe the synthesis and the characterization of the resulting coordination compounds. The yields of the reactions vary from a minimum of 21% to a maximum of 82%, using a fast and easy procedure. Nuclear Magnetic Resonance (NMR) and Infra Red (IR) spectroscopy, mass spectrometry, elemental analysis, and X-ray Diffraction (XRD) confirm the formation of stable compounds in all cases and a ligand-to-metal 2:1 stoichiometry with both cations. In addition, we further investigated their chemical and biological characteristics, via UV-visible titrations, stability tests, and cytotoxicity and antibiotic assays. The results confirm a strong stability in all explored conditions, which suggests that these compounds are more suitable for radio imaging applications rather than for antitumoral or antimicrobic ones.

Interaction of gallium, indium, and vanadyl curcumin complexes with hen egg-white lysozyme (HEWL): Mechanistic aspects and evaluation of antiamyloidogenic activity.

Many proteins and peptides can aggregate into amyloid fibrils with high-ordered and cross-ß rich structure characteristics. Amyloid deposition is a common feature of neurodegenerative diseases called amyloidosis. Various natural polyphenolic compounds such as curcumin exhibited antiamyloidogenic activities, but less researches were focused on the metal complexes of these compounds. In this study, the inhibitory effects of gallium curcumin (Ga(cur)3), indium curcumin (In(cur)3), and vanadyl curcumin (VO(cur)2) on the amyloid fibrillation of hen egg white lysozyme (HEWL) have been investigated. Moreover, the details of binding interactions of these metal complexes with HEWL have been explored. The results of fluorescence quenching analyses revealed that In(cur)3 and VO(cur)2 have much higher binding affinities than Ga(cur)3 toward HEWL. The interactions of these metal complexes were accompanied by partial conformational changes in the tertiary structure of HEWL. The kinetic curves of the fibrillation process demonstrated that In(cur)3 and VO(cur)2 have higher inhibitory effects than Ga(cur)3 on the amyloid fibrillation of HEWL. The strength of binding to HEWL is completely in accordance with inhibitory activities of these metal complexes of curcumin.

Novel lactoferrin-conjugated gallium complex to treat Pseudomonas aeruginosa wound infection.

Pseudomonas aeruginosa is one of the leading causes of opportunistic infections such as chronic wound infection that could lead to multiple organ failure and death. Gallium (Ga3+) ions are known to inhibit P. aeruginosa growth and biofilm formation but require carrier for localized controlled delivery. Lactoferrin (LTf), a two-lobed protein, can deliver Ga3+ at sites of infection. This study aimed to develop a Ga-LTf complex for the treatment of wound infection. The characterisation of the Ga-LTf complex was conducted using differential scanning calorimetry (DSC), Infra-Red (FTIR) and Inductive Coupled Plasma Optical Emission Spectrometry (ICP-OES). The antibacterial activity was assessed by agar disc diffusion, liquid broth and biofilm inhibition assays using the colony forming units (CFUs). The healing capacity and biocompatibility were evaluated using a P.aeruginosa infected wound in a rat model. DSC analyses showed thermal transition consistent with apo-lactoferrin; FTIR confirmed the complexation of gallium to lactoferrin. ICP-OES confirmed the controlled local delivery of Ga3+. Ga-LTf showed a 0.57 log10 CFUs reduction at 24 h compared with untreated control in planktonic liquid broth assay. Ga-LTf showed the highest antibiofilm activity with a 2.24 log10 CFUs reduction at 24 h. Furthermore, Ga-LTf complex is biocompatible without any adverse effect on brain, kidney, liver and spleen of rats tested in this study. Ga-LTf can be potentially promising novel therapeutic agent to treat pathogenic bacterial infections.

Metallic Gallium Droplets Exhibit Poor Antibacterial Properties.

The rise of antibiotic resistance in pathogenic bacteria requires new therapeutics to be developed. Several metallic nanoparticles such as those made from silver, copper, and zinc have shown significant antibacterial activity, in part due to metal ion leaching. Ga3+ containing compounds have also been shown to have antibacterial properties. Accordingly, it is estimated that metallic Ga droplets may be antibacterial, and some studies to date have confirmed this. Here, multiple concentrations of Ga droplets were tested against the antibiotic resistant Gram-positive bacteria methicillin-resistantStaphylococcus aureus (MRSA) and the Gram-negative bacteria Pseudomonas aeruginosa (P. aeruginosa) Despite a high concentration (2 mg/mL), Ga droplets had only modest antibacterial activity against both bacteria after 24 h of interaction. Finally, we demonstrated that Ga droplets were easily functionalized through a galvanic replacement reaction to develop antibacterial particles with copper and silver demonstrating a total detectable reduction of MRSA and >96% reduction ofP. aeruginosa. Altogether, these results contradict previous literature and show that Ga droplets demonstrate no antibacterial activity at concentrations comparable to those of conventional antibiotics and well-established antibacterial nanomaterials and only modest antibacterial activity at very high concentrations. However, we demonstrate that their antibacterial activity can be easily enhanced by functionalization.

Atomistic modelling and NMR studies reveal that gallium can target the ferric PQS uptake system in P. aeruginosa biofilms.

Intravenous gallium nitrate therapy is a novel therapeutic strategy deployed to combat chronic Pseudomonas aeruginosa biofilm infections in the lungs of cystic fibrosis (CF) patients by interfering with iron (Fe3+) uptake. The therapy is a source of Ga3+, which competes with Fe3+ for siderophore binding, subsequently disrupting iron metabolism and inhibiting biofilm proliferation in vivo. It was recently demonstrated that the Pseudomonas quinolone signal (PQS) can chelate Fe3+ to assist in bacterial iron uptake. However, it is unknown whether exogenous gallium also targets [Fe(PQS)3] uptake, which, in turn, would extend the mechanism of gallium therapy beyond siderophore competition, potentially supporting use of the therapy against P. aeruginosa mutants deficient in siderophore uptake proteins. To that end, the thermodynamic feasibility of iron-for-gallium cation exchange into [Fe(PQS)3] was evaluated using quantum chemical density functional theory (DFT) modelling and verified experimentally using 1H nuclear magnetic resonance (NMR). We demonstrate here that Ga3+ can strongly bind to three PQS molecules and, furthermore, displace and substitute Fe3+ from the native chelate pocket within PQS complexes, through a Trojan horse mechanism, retaining the key structural features present within the native ferric complex. As such, [Fe(PQS)3] complexes, in addition to ferric-siderophore complexes, represent another target for gallium therapy.

Gallium-Doped Hydroxyapatite: Shape Transformation and Osteogenesis Activity.

In this study, we employed a chemical precipitation method to successfully synthesize nanoparticles of gallium-doped hydroxyapatite (Ga-HAp). The microstructure of Ga-HAp was precisely tailored by modulating the concentration of gallium ions. Our findings unequivocally demonstrate that gallium ions exert a pronounced inhibitory influence on the growth of HAp crystals, and this inhibitory potency exhibits a direct correlation with the concentration of gallium. Furthermore, gallium ions facilitate the metamorphosis of HAp nanoparticles, transitioning them from nanoneedles to nanosheets. It is worth noting, however, that gallium ions exhibit a limited capacity to substitute for calcium ions within the crystal lattice of HAp, with the maximum substitution rate capped at 4.85%. Additionally, gallium plays a pivotal role in constraining the release of ions from HAp, and this behavior remains consistent across samples with varying Ga doping concentrations. Our in vitro experiments confirm that Ga-doped HAp amplifies both the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells.

First Gallium and Indium Crystal Structures of Curcuminoid Homoleptic Complexes: All-Different Ligand Stereochemistry and Cytotoxic Potential.

The crystal structure determination of metal complexes of curcuminoids is a relevant topic to assess their unequivocal molecular structure. We report herein the first two X-ray crystal structures of homoleptic metal complexes of a curcuminoid, namely Dimethoxycurcumin (DiMeOC), with gallium and indium. Such successful achievement can be attributed to the suppression of interactions from the phenolic groups, which favor an appropriate molecular setup, rendering Dimethoxycurcumin gallium ((DiMeOC)2-Ga) and Dimethoxycurcumin indium ((DiMeOC)3-In) crystals. Surprisingly, the conformation of ligands in the crystal structures shows differences in each metal complex. Thus, the ligands in the (DiMeOC)2-Ga complex show two different conformers in the two molecules of the asymmetric unit. However, the ligands in the (DiMeOC)3-In complex exhibit three different conformations within the same molecule of the asymmetric unit, constituting the first such case described for an ML3 complex. The cytotoxic activity of the (DiMeOC)2-Ga complex is 4-fold higher than cisplatin against the K562 cell line and has comparable activity towards U251 and PC-3 cell lines. Interestingly, this complex exhibit three times lesser toxicity than cisplatin and even slightly lesser cytotoxicity than curcumin itself.

Gallium-based metal-organic frameworks loaded with antimicrobial peptides for synergistic killing of drug-resistant bacteria.

Increased antibiotic resistance has made bacterial infections a global concern, which requires novel non-antibiotic-dependent antibacterial strategies to address the menace. Antimicrobial peptides (AMPs) are a promising antibiotic alternative, whose antibacterial mechanism is mainly to destroy the membrane of bacteria. Gallium ions exhibit an antibacterial effect by interfering with the iron metabolism of bacteria. With the rapid development of nanotechnology, it is worth studying the potential of gallium-AMP-based nanocomposites for treating bacterial infections. Herein, novel gallium-based metal-organic frameworks (MOFs) were synthesized at room temperature, followed by in situ loading of the model AMP melittin. The obtained nanocomposites exhibited stronger antibacterial activity than pure MEL and gallium ions, achieving the effects of "one plus one is greater than two". Moreover, the nanocomposites showed favorable biocompatibility and accelerated healing of a wound infected by methicillin-resistant Staphylococcus aureus by down-regulation of inflammatory cytokines IL-6 and TNF-α. This work presents an innovative antibacterial strategy to overcome the antibiotic resistance crisis and expand the application of AMPs.

In Vivo Trafficking of the Anticancer Drug Tris(8-Quinolinolato) Gallium (III) (KP46) by Gallium-68/67 PET/SPECT Imaging.

KP46 (tris(hydroxyquinolinato)gallium(III)) is an experimental, orally administered anticancer drug. Its absorption, delivery to tumours, and mode of action are poorly understood. We aimed to gain insight into these issues using gallium-67 and gallium-68 as radiotracers with SPECT and PET imaging in mice. [67Ga]KP46 and [68Ga]KP46, compared with [68Ga]gallium acetate, were used for logP measurements, in vitro cell uptake studies in A375 melanoma cells, and in vivo imaging in mice bearing A375 tumour xenografts up to 48 h after intravenous (tracer level) and oral (tracer and bulk) administration. 68Ga was more efficiently accumulated in A375 cells in vitro when presented as [68Ga]KP46 than as [68Ga]gallium acetate, but the reverse was observed when intravenously administered in vivo. After oral administration of [68/67Ga]KP46, absorption of 68Ga and 67Ga from the GI tract and delivery to tumours were poor, with the majority excreted in faeces. By 48 h, low but measurable amounts were accumulated in tumours. The distribution in tissues of absorbed radiogallium and octanol extraction of tissues suggested trafficking as free gallium rather than as KP46. We conclude that KP46 likely acts as a slow releaser of gallium ions which are inefficiently absorbed from the GI tract and trafficked to tissues, including tumour and bone.

Enhanced antibacterial activity of dimethyl gallium quinolinolates toward drug-resistant Klebsiella pneumoniae in low iron environments.

A series of dimethylgallium quinolinolate [GaMe2L] (L = 5-chloroquinolinolate, 5, 7-dichloroquinolinolate, 5, 7-dibromoquinolinolate or 5, 7-doiodoquinolinolate) complexes, shown previously to be active toward the Leishmania parasite, have been studied for their antibacterial activity toward a reference and drug resistant strain of Klebsiella pneumoniae (KP). The assays were conducted in standard iron-rich LB media and in the iron depleted RPMI and RPMI-HS media to better understand the effect of Fe concentration on the activity of the Ga complexes. In LB broth the parent quinolinols and the gallium complexes were inactive up to the highest concentration tested, 100 µM. In the more physiologically relevant 'iron-poor' RPMI-HS media the quinolonols remained inactive, however, the gallium complexes showed exceptional activity in the range 48-195 nM. Only in RPMI without any added HS did both the quinolinols and the gallium complexes show good activity. The significant differences in activity across the various media types suggest that the unnaturally high iron content of conventional LB media may provide false negative results for potentially potent Ga therapeutics. A protein binding assay on the organometallic gallium complexes showed a much slower uptake of Ga by Fe-binding proteins than is typically observed for gallium salts. This indicates that their greater lipophilicity and greater hydrolytic stability could account for their increased biological activity in RPMI-HS media.

Comparative proteomics unveils the bacteriostatic mechanisms of Ga(III) on the regulation of metabolic pathways in Pseudomonas aeruginosa.

Gallium has a long history as a chemotherapeutic agent. The mechanisms of action of Ga(III)-based anti-infectives are different from conventional antibiotics, which primarily result from the chemical similarities of Ga(III) with Fe(III) and substitution of gallium into iron-dependent biological pathways. However, more aspects of the molecular mechanisms of Ga(III) against human pathogens, especially the effects on bacterial metabolic processes, remain to be understood. Herein, by using conventional quantitative proteomics, we identified the protein changes of Pseudomonas aeruginosa (P. aeruginosa) in response to Ga(NO3)3 treatment. We show that Ga(III) exhibits bacteriostatic mode of action against P. aeruginosa through affecting the expressions of a number of key enzymes in the main metabolic pathways, including glycolysis, TCA cycle, amino acid metabolism, and protein and nucleic acid biosynthesis. In addition, decreased expressions of proteins associated with pathogenesis and virulence of P. aeruginosa were also identified. Moreover, the correlations between protein expressions and metabolome changes in P. aeruginosa upon Ga(III) treatment were identified and discussed. Our findings thus expand the understanding on the antimicrobial mechanisms of Ga(III) that shed light on enhanced therapeutic strategies. BIOLOGICAL SIGNIFICANCE: Mounting evidence suggest that the efficacy and resistance of clinical antibiotics are closely related to the metabolic homeostasis in bacterial pathogens. Ga(III)-based compounds have been repurposed as antibacterial therapeutic candidates against antibiotics resistant pathogens, and represent a safe and promising treatment for clinical human infections, while more thorough understandings of how bacteria respond to Ga(III) treatment are needed. In the present study, we provide evidences at the proteome level that indicate Ga(III)-induced metabolic perturbations in P. aeruginosa. We identified and discussed the interference of Ga(III) on the expressions and activities of enzymes in the main metabolic pathways in P. aeruginosa. In view of our previous report that the antimicrobial efficacy of Ga(III) could be modulated according to Ga(III)-induced metabolome changes in P. aeruginosa, our current analyses may provide theoretical basis at the proteome level for the development of efficient gallium-based therapies by exploiting bacterial metabolic mechanisms.

Gallium reactivates first and second generation quinolone antibiotics towards drug-resistant Klebsiella pneumoniae.

Herein, we report on a series of homoleptic [GaL3] and heteroleptic organometallic [GaMe2L] complexes of inactive quinolone antibiotics; nalidixic acid, oxolinic acid and norfloxacin with their antibacterial activity (MIC 0.024-0.781 µM) towards four multi-drug resistant strains of Klebsiella pneumoniae through complexation to gallium.

Antioxidative and antibacterial gallium (III)-phenolic coating for enhanced osseointegration of titanium implants via pro-osteogenesis and inhibiting osteoclastogenesis.

Improving the ability of implants to integrate with natural bone tissue at the initial stage of implantation remains a huge challenge because bone-to-implant interfaces are often accompanied by abnormal microenvironments with infection, reactive oxygen species (ROS) and unbalanced bone homeostasis. In this study, a multifunctional coating was fabricated on the basis of gallium (III)-phenolic networks. It is easily obtained by immersing the implants into a mixed solution of tannic acids (TAs) and gallium ions. The thickness of the coating can be precisely controlled by adjusting the number and time of immersion experiments. The resulting coating displays excellent near-infrared photothermal property. As the coating degrades, TAs and gallium ions with low concentration are released from the coating, which is more rapid in acidic and oxidative stress microenvironments. Photothermal performance as well as released TAs and gallium ions give the coating outstanding broad-spectrum antibacterial ability. Furthermore, the coating effectively reduces intracellular ROS of osteoblasts. In vitro and in vivo experiments demonstrate the capability of the coating enhancing implants' osseointegration via pro-osteogenesis and inhibiting osteoclastogenesis. The findings imply that gallium (III)-phenolic coating holds great promise to promote implant osseointegration by rescuing abnormal microenvironments of infection, oxidative stress and unbalanced bone homeostasis.

Biocompatible Gallium Nanodots against Drug-Resistant Bacterial Pneumonia and Liver Abscess.

Resistant bacterial infection remains a severe public health threat, and conventional antibiotic drugs work poorly in effectively treating infectious diseases. Here, we developed gallium-based nanodots (Ga NDs), consisting of specific disruption of bacterial iron ability, to treat multidrug-resistant (MDR) Gram-negative bacteria-infected diseases. The Ga NDs significantly suppress the proliferation of two typical MDR bacteria strains (P. aeruginosa and ESBL E. coli) compared with clinically used antibacterial drugs, including penicillin and levofloxacin. Ga NDs could also disrupt the biofilms of these two bacterial strains. In P. aeruginosa infected pneumonia and ESBL E. coli infected acute liver abscess models, the Ga NDs enable substantial inhibition of bacterial growth and reduce the organs' inflammation that resulted in significant improvement of survival. Further, the Ga NDs demonstrated excellent biocompatibility and biosafety characteristics. Together, we believe that our gallium containing nanotherapeutics are expected to be developed into promising alternative therapies to combat drug-resistant bacterial infection.

Gallium(III)- and Thallium(III)-Encapsulated Polyoxopalladates: Synthesis, Structure, Multinuclear NMR, and Biological Activity Studies.

Three gallium(III)- and thallium(III)-containing polyoxopalladates (POPs) have been synthesized and structurally characterized in the solid state and in solution, namely, the phosphate-capped 12-palladate nanocubes [XPd12O8(PO4)8]13- (X = GaIII, GaPd12P8; X = TlIII, TlPd12P8) and the 23-palladate double-cube [Tl2IIIPd23P14O70(OH)2]20- (Tl2Pd23P14). The cuboid POPs, GaPd12P8 and TlPd12P8, are solution stable as verified by the respective 31P, 71Ga, and 205Tl nuclear magnetic resonance (NMR) spectra. Of prime interest, the spin-spin coupling schemes allowed for an intimate study of the solution behavior of the TlIII-containing POPs via a combination of 31P and 205Tl NMR, including the stoichiometry of the major fragments of Tl2Pd23P14. Moreover, biological studies demonstrated the antitumor and antiviral activity of GaPd12P8 and TlPd12P8, which were validated to be as efficient as cis-platinum against human melanoma and acute promyelocytic leukemia cells. Furthermore, GaPd12P8 and TlPd12P8 exerted inhibitory activity against two herpetic viruses, HSV-2 and HCMV, in a dose-response manner.

Gallium Liquid Metal: Nanotoolbox for Antimicrobial Applications.

The proliferation of drug resistance in microbial pathogens poses a significant threat to human health. Hence, treatment measures are essential to surmount this growing problem. In this context, liquid metal nanoparticles are promising. Gallium, a post-transition metal notable for being a liquid at physiological temperature, has drawn attention for its distinctive properties, high antimicrobial efficacy, and low toxicity. Moreover, gallium nanoparticles demonstrate anti-inflammatory properties in immune cells. Gallium can alloy with other metals and be prepared in various composites to modify and tailor its characteristics and functionality. More importantly, the bactericidal mechanism of gallium liquid metal could sidestep the threat of emerging drug resistance mechanisms. Building on this rationale, gallium-based liquid metal nanoparticles can enable impactful and innovative strategic pathways in the battle against antimicrobial resistance. This review outlines the characteristics of gallium-based liquid metals at the nanoscale and their corresponding antimicrobial mechanisms to provide a comprehensive yet succinct overview of their current antimicrobial applications. In addition, challenges and opportunities that require further research efforts have been identified and discussed.

Deferiprone-gallium-protoporphyrin (IX): A promising treatment modality against Mycobacterium abscessus.

Non-Tuberculous Mycobacterial Pulmonary Disease (NTM-PD) caused by Mycobacterium abscessus is a frequent complication in patients with cystic fibrosis (CF) that worsens lung function over time. Currently, there is no cure for NTM-PD, hence new therapies are urgently required. Disrupting bacterial iron uptake pathways using gallium-protoporphyrin (IX) (GaPP), a heme analog, has been proposed as a novel antibacterial approach to tackle multi-drug resistant M. abscessus. However, the antibacterial activity of GaPP has been tested only in iron-deficient media, which cannot accurately mirror the potential activity in vivo. Herein, we investigated the potential synergistic activity between GaPP and the iron-chelating agent deferiprone (Def) in regular media against M. abscessus-infected macrophages. The safety of the treatment was assessed in vitro using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in Nuli-1 and THP-1 cell lines. Def-GaPP had synergistic activity against M. abscessus-infected macrophages where 10 mM-12.5 mg/L of Def-GaPP reduced the viability by up to 0.9 log10. Furthermore, Def-GaPP showed no cytotoxicity to Nuli-1 and THP-1 cell lines at the effective antibacterial concentrations (10 mM-12.5 mg/L) of Def- GaPP. These data encourage future investigation of Def-GaPP as a novel antimicrobial against NTM-PD.