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Host responses – autophagy, cell death, and inflammation – limit the growth of bacterial pathogens while minimizing tissue damage. During the early stages of infection, Mycobacterium tuberculosis ( Mtb ) thwarts these and other innate immune defense mechanisms in alveolar macrophages (AMs) derived from the yolk sac; in later stages, it circumvents defenses in recruited mononuclear cells (MNCs) and survives within them despite additional cytokine stimulation from recruited T cells. The mechanisms that drive variable rates of Mtb growth in different macrophage subtypes and how Mtb manipulates inflammatory responses to grow within innate immune cells remain obscure. Here we explored the role of the host factor, Tax-1 binding protein 1 (Tax1bp1), an autophagy receptor that targets pathogens for degradation through selective autophagy and terminates pro-inflammatory cytokine responses. Unexpectedly, we found that Tax1bp1-deficient mice were less susceptible to Mtb infection, and generated reduced inflammatory cytokine responses, compared to wild-type mice; the same mutant mice exhibited decreased growth of, and inflammatory cytokine responses to, Listeria monocytogenes , suggesting that Tax1bp1 plays a role in host responses to multiple intracellular pathogens. Contrary to our previous ex vivo findings in bone marrow-derived macrophages (BMDMs), in vivo growth of Mtb in AMs and a subset of recruited MNCs was more limited in mice lacking Tax1bp1 relative to wild-type mice. To better understand these differences, we performed global protein abundance measurements in mock- and Mtb- infected AM samples ex vivo from wild-type mice. These experiments revealed that Tax1bp1 protein abundance does not significantly change early after infection in AMs but does in BMDMs; moreover, early after infection, Tax1bp1-deficiency reduced necrotic-like cell death -- an outcome that favors Mtb replication -- in AMs but not BMDMs. Together, these results show that deficiency of Tax1bp1 plays a crucial, cell type-specific role in linking the regulation of autophagy, cell death, and anti-inflammatory host responses and overall reducing bacterial growth.

Although iron is essential for all forms of life, it is also potentially toxic to cells as the increased and unregulated iron uptake can catalyze the Fenton reaction to produce reactive oxygen species (ROS), leading to lipid peroxidation of membranes, oxidation of proteins, cleavage of DNA and even activation of apoptotic cell death pathways. We demonstrate that Fe(hinok)3 (hinok = 2-hydroxy-4-isopropyl-2,4,6-cycloheptatrien-1-one), a neutral Fe(III) complex with high lipophilicity is capable of bypassing the regulation of iron trafficking to disrupt cellular iron homeostasis; thus, harnessing remarkable anticancer activity against a panel of five different cell lines, including Pt-sensitive ovarian cancer cells (A2780; IC50 = 2.05 ± 0.90 μM or 1.20 μg/mL), Pt-resistant ovarian cancer cells (A2780cis; IC50 = 0.92 ± 0.73 μM or 0.50 μg/mL), ovarian cancer cells (SKOV-3; IC50 = 1.23 ± 0.01 μM or 0.67 μg/mL), breast cancer cells (MDA-MB-231; IC50 = 3.83 ± 0.12 μM or 2.0 μg/mL) and lung cancer cells (A549; IC50 = 1.50 ± 0.32 μM or 0.82 μg/mL). Of great significance is that Fe(hinok)3 exhibits unusual selectivity toward the normal HEK293 cells and the ability to overcome the Pt resistance in the Pt-resistant mutant ovarian cancer cells of A2780cis.

A quarter of humanity is estimated to have been exposed to Mycobacterium tuberculosis ( Mtb ) with a 5–10% risk of developing tuberculosis (TB) disease. Variability in responses to Mtb infection could be due to host or pathogen heterogeneity. Here, we focused on host genetic variation in a Peruvian population and its associations with gene regulation in monocyte-derived macrophages and dendritic cells (DCs). We recruited former household contacts of TB patients who previously progressed to TB (cases, n = 63) or did not progress to TB (controls, n = 63). Transcriptomic profiling of monocyte-derived DCs and macrophages measured the impact of genetic variants on gene expression by identifying expression quantitative trait loci (eQTL). We identified 330 and 257 eQTL genes in DCs and macrophages (False Discovery Rate (FDR) < 0.05), respectively. Four genes in DCs showed interaction between eQTL variants and TB progression status. The top eQTL interaction for a protein-coding gene was with FAH , the gene encoding fumarylacetoacetate hydrolase, which mediates the last step in mammalian tyrosine catabolism. FAH expression was associated with genetic regulatory variation in cases but not controls. Using public transcriptomic and epigenomic data of Mtb -infected monocyte-derived dendritic cells, we found that Mtb infection results in FAH downregulation and DNA methylation changes in the locus. Overall, this study demonstrates effects of genetic variation on gene expression levels that are dependent on history of infectious disease and highlights a candidate pathogenic mechanism through pathogen-response genes. Furthermore, our results point to tyrosine metabolism and related candidate TB progression pathways for further investigation.

Four Zn(II) complexes containing a pyridyl triazine core (L1 = 3-(2-pyridyl)-5,6-di(2-furyl)-1,2,4-triazine-5′,5″-disulfonic acid disodium salt and L2 = 3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine-4′,4″-disulfonic acid sodium salt) were synthesized, and their chemical formulas were finalized as [Zn(L1)Cl2]·5H2O·ZnCl2 (1), [Zn(L1)2Cl2]·4H2O·2CH3OH (2), [Zn(L2)Cl2]·3H2O·CH3OH (3), and [Zn(L2)2Cl2] (4). The synthesized complexes are water soluble, making them good candidates for biological applications. All four complexes have been characterized by elemental analysis and 1H NMR, IR, and UV-Vis spectroscopy. The IR stretching frequency of N=N and C=N bonds of complexes 1–4 have shifted to lower frequencies in comparison with free ligands, and a bathochromic shift was observed in UV-Vis spectra of all four complexes. The binding studies of ligands and complexes 1–4 with bovine serum albumin (BSA) resulted binding constants (Kb) of 3.09 × 104 M−1, 12.30 × 104 M−1, and 16.84 × 104 M−1 for ferene, complex 1, and complex 2, respectively, indicating potent serum distribution via albumins.

8-Hydroxyquinoline (8-hq) exhibits potent antimicrobial activity against Staphylococcus aureus (SA) bacteria with MIC = 16.0–32.0 µM owing to its ability to chelate metal ions such as Mn2+, Zn2+, and Cu2+ to disrupt metal homeostasis in bacterial cells. We demonstrate that Fe(8-hq)3, the 1:3 complex formed between Fe(III) and 8-hq, can readily transport Fe(III) across the bacterial cell membrane and deliver iron into the bacterial cell, thus, harnessing a dual antimicrobial mechanism of action that combines the bactericidal activity of iron with the metal chelating effect of 8-hq to kill bacteria. As a result, the antimicrobial potency of Fe(8-hq)3 is significantly enhanced in comparison with 8-hq. Resistance development by SA toward Fe(8-hq)3 is considerably delayed as compared with ciprofloxacin and 8-hq. Fe(8-hq)3 can also overcome the 8-hq and mupirocin resistance developed in the SA mutant and MRSA mutant bacteria, respectively. Fe(8-hq)3 can stimulate M1-like macrophage polarization of RAW 264.7 cells to kill the SA internalized in such macrophages. Fe(8-hq)3 exhibits a synergistic effect with both ciprofloxacin and imipenem, showing potential for combination therapies with topical and systemic antibiotics for more serious MRSA infections. The in vivo antimicrobial efficacy of a 2% Fe(8-hq)3 topical ointment is confirmed by the use of a murine model with skin wound infection by bioluminescent SA with a reduction of the bacterial burden by 99 ± 0.5%, indicating that this non-antibiotic iron complex has therapeutic potential for skin and soft tissue infections (SSTIs).

Although it has no known biochemical role in living organisms, bismuth has been used to treat syphilis, diarrhea, gastritis and colitis for almost a century due to its nontoxic nature to mammalian cells. When prepared via a top-down sonication route from a bulk sample, bismuth subcarbonate (BiO)2CO3 nanoparticles (NPs) with an average size of 5.35 ± 0.82 nm exhibit broad-spectrum potent antibacterial activity against both the gram-positive and gram-negative bacteria including methicillin-susceptible Staphylococcus aureus (DSSA), methicillin-resistant Staphylococcus aureus (MRSA), drug-susceptible Pseudomonas aeruginosa (DSPA) and multidrug-resistant Pseudomonas aeruginosa (DRPA). Specifically, the minimum inhibitory concentrations (MICs) are 2.0 µg/mL against DSSA and MRSA and 0.75 µg/mL against DSPA and DRPA. In sharp contrast to ciprofloxacin, AgNPs and meropenem, (BiO)2CO3 NPs show no sign of developing Bi-resistant phenotypes after 30 consecutive passages. On the other hand, such NPs can readily overcome the resistance to ciprofloxacin, AgNPs and meropenem in DSPA. Finally, the combination of (BiO)2CO3 NPs and meropenem shows a synergistic effect with the fractional inhibitory concentration (FIC) index of 0.45.

Although it has no known biochemical role in living organisms, bismuth has been used to treat syphilis, diarrhea, gastritis and colitis for almost a century due to its nontoxic nature to mammalian cells. When prepared via a top-down sonication route from a bulk sample, bismuth subcarbonate (BiO) CO nanoparticles (NPs) with an average size of 5.35 ± 0.82 nm exhibit broad-spectrum potent antibacterial activity against both the gram-positive and gram-negative bacteria including methicillin-susceptible (DSSA), methicillin-resistant (MRSA), drug-susceptible (DSPA) and multidrug-resistant (DRPA). Specifically, the minimum inhibitory concentrations (MICs) are 2.0 µg/mL against DSSA and MRSA and 0.75 µg/mL against DSPA and DRPA. In sharp contrast to ciprofloxacin, AgNPs and meropenem, (BiO) CO NPs show no sign of developing Bi-resistant phenotypes after 30 consecutive passages. On the other hand, such NPs can readily overcome the resistance to ciprofloxacin, AgNPs and meropenem in DSPA. Finally, the combination of (BiO) CO NPs and meropenem shows a synergistic effect with the fractional inhibitory concentration (FIC) index of 0.45.

Although it has no known biochemical role in living organisms, bismuth has been used to treat syphilis, diarrhea, gastritis and colitis for almost a century due to its nontoxic nature to mammalian cells. When prepared via a top-down sonication route from a bulk sample, bismuth subcarbonate (BiO)[sub.2]CO[sub.3] nanoparticles (NPs) with an average size of 5.35 ± 0.82 nm exhibit broad-spectrum potent antibacterial activity against both the gram-positive and gram-negative bacteria including methicillin-susceptible Staphylococcus aureus (DSSA), methicillin-resistant Staphylococcus aureus (MRSA), drug-susceptible Pseudomonas aeruginosa (DSPA) and multidrug-resistant Pseudomonas aeruginosa (DRPA). Specifically, the minimum inhibitory concentrations (MICs) are 2.0 µg/mL against DSSA and MRSA and 0.75 µg/mL against DSPA and DRPA. In sharp contrast to ciprofloxacin, AgNPs and meropenem, (BiO)[sub.2]CO[sub.3] NPs show no sign of developing Bi-resistant phenotypes after 30 consecutive passages. On the other hand, such NPs can readily overcome the resistance to ciprofloxacin, AgNPs and meropenem in DSPA. Finally, the combination of (BiO)[sub.2]CO[sub.3] NPs and meropenem shows a synergistic effect with the fractional inhibitory concentration (FIC) index of 0.45.

8-Hydroxyquinoline (8-hq) exhibits potent antimicrobial activity against Staphylococcus aureus (SA) bacteria with MIC = 16.0-32.0 µM owing to its ability to chelate metal ions such as Mn[sup.2+], Zn[sup.2+,] and Cu[sup.2+] to disrupt metal homeostasis in bacterial cells. We demonstrate that Fe(8-hq)[sub.3], the 1:3 complex formed between Fe(III) and 8-hq, can readily transport Fe(III) across the bacterial cell membrane and deliver iron into the bacterial cell, thus, harnessing a dual antimicrobial mechanism of action that combines the bactericidal activity of iron with the metal chelating effect of 8-hq to kill bacteria. As a result, the antimicrobial potency of Fe(8-hq)[sub.3] is significantly enhanced in comparison with 8-hq. Resistance development by SA toward Fe(8-hq)[sub.3] is considerably delayed as compared with ciprofloxacin and 8-hq. Fe(8-hq)[sub.3] can also overcome the 8-hq and mupirocin resistance developed in the SA mutant and MRSA mutant bacteria, respectively. Fe(8-hq)[sub.3] can stimulate M1-like macrophage polarization of RAW 264.7 cells to kill the SA internalized in such macrophages. Fe(8-hq)[sub.3] exhibits a synergistic effect with both ciprofloxacin and imipenem, showing potential for combination therapies with topical and systemic antibiotics for more serious MRSA infections. The in vivo antimicrobial efficacy of a 2% Fe(8-hq)[sub.3] topical ointment is confirmed by the use of a murine model with skin wound infection by bioluminescent SA with a reduction of the bacterial burden by 99 ± 0.5%, indicating that this non-antibiotic iron complex has therapeutic potential for skin and soft tissue infections (SSTIs).

Crosstalk between autophagy, host cell death, and inflammatory host responses to bacterial pathogens enables effective innate immune responses that limit bacterial growth while minimizing coincidental host damage. ( ) thwarts innate immune defense mechanisms in alveolar macrophages (AMs) during the initial stages of infection and in recruited bone marrow-derived cells during later stages of infection. However, how protective inflammatory responses are achieved during infection and the variation of the response in different macrophage subtypes remain obscure. Here, we show that the autophagy receptor Tax1bp1 plays a critical role in enhancing inflammatory cytokine production and increasing the susceptibility of mice to infection. Surprisingly, although Tax1bp1 restricts growth during infection of bone marrow-derived macrophages (BMDMs) (Budzik 2020) and terminates cytokine production in response to cytokine stimulation or viral infection, Tax1bp1 instead promotes growth in AMs, neutrophils, and a subset of recruited monocyte-derived cells from the bone marrow. Tax1bp1 also leads to increases in bacterial growth and inflammatory responses during infection of mice with , an intracellular pathogen that is not effectively targeted to canonical autophagy. In infected AMs but not BMDMs, Tax1bp1 enhances necrotic-like cell death early after infection, reprogramming the mode of host cell death to favor replication in AMs. Tax1bp1's impact on host cell death is a mechanism that explains Tax1bp1's cell type-specific role in the control of growth. Similar to deficiency in AMs, the expression of phosphosite-deficient Tax1bp1 restricts growth. Together, these results show that Tax1bp1 plays a crucial role in linking the regulation of autophagy, cell death, and pro-inflammatory host responses and enhancing susceptibility to bacterial infection.