Iron- and heme-uptake pathways metabolism are promising targets for the development of new antimicrobial agents, as their disruption would lead to nutritional iron starvation inhibition bacterial growth. Salts gallium(III) (Ga), an mimetic metal, disrupt iron-dependent biological processes by binding iron-utilizing proteins competing with uptake siderophore-mediated systems. Ga porphyrins, heme complexes, heme-utilizing hemoproteins. Because Ga(NO3)3 porphyrin different ion acquisition...

New treatments and novel drugs are required to counter the growing problem of drug-resistant strains Mycobacterium tuberculosis (M.tb). Our approach against drug resistant M.tb, as well other intracellular pathogens, is by targeted delivery using nanoformulations already in use, development. Among latter gallium (III) (Ga)-based compounds. In current work, six different types Ga rifampin nanoparticles were prepared such a way enhance targeting M.tb infected-macrophages. They then tested for...

Nontuberculous Mycobacteria (NTM) are a heterogeneous group of environmental microorganisms with distinct human pathogenesis. Their incidence and prevalence rising worldwide, due in part to elevated antimicrobial resistance which complicates treatment potential successful outcomes. Although information exists on the clinical significance NTMs, little is known about host immune response infection. NTM infections alter macrophage mitochondrial capacity decrease ATP production, efficient...

Plasmodium falciparum lactate dehydrogenase (pfLDH) is a key enzyme for energy generation of malarial parasites and potential antimalarial chemotherapeutic target. It known that the oxamate moiety, pyruvate analog, alone shows higher inhibition against pfLDH than human LDHs, suggesting it can be used development selective inhibitors. Oxamic acid derivatives were designed synthesized. Derivatives 5 7 demonstrated activities with IC50 values 3.13 1.75 μM, respectively, have 59- 7-fold...

Treatment of individuals coinfected with human immunodeficiency virus (HIV) type 1 and Mycobacterium tuberculosis is challenging due to the prolonged treatment requirements, drug toxicity, emergence resistance. Mononuclear phagocytes (MP; macrophages) are one natural reservoirs for both HIV M. Here, coinfection was studied by preloading macrophages MP-targeted gallium (Ga) nanoparticles limit subsequent simultaneous infection Ga provided sustained release 15 days significantly inhibited...

Iron/heme acquisition systems are critical for microorganisms to acquire iron from the human host, where sources limited due nutritional immune system and insolubility of ferric form iron. Prior work has shown that a variety gallium compounds can interfere with bacterial acquisition. This study explored intra- extracellular antimicrobial activities protoporphyrin (GaPP), mesoporphyrin (GaMP), nanoparticles encapsulating GaPP or GaMP against Gram-negative pathogens Pseudomonas aeruginosa...

There is an urgent need for new effective and safe antibiotics active against pathogenic mycobacterial species. Gallium (Ga) nitrate (Ga(NO3)3) Ga porphyrin (GaPP) have each been shown to inhibit the growth of a variety The Ga(III) ion derived from Ga(NO3)3 has potential disrupt Fe(III) uptake mechanisms utilization, including replacing iron (Fe) in site enzymes, resulting disruption function. Similarly, noniron metalloporphyrins such as heme mimetics, which can be transported across...

Lactate dehydrogenase (LDH) is a key enzyme in the glycolytic pathway of Plasmodium falciparum (pf) and has several unique amino acids, related to other LDHs, at active site, making it an attractive target for antimalarial agents. Oxamate, competitive inhibitor, shows high substrate affinity pfLDH. This class compounds been viewed as potential Thus, we have developed effective automated synthetic strategy rapid synthesis oxamic acid ester libraries screen lead inhibitors. One hundred...

The nontuberculous mycobacterial (NTM) pathogens, M. avium complex (MAC) and abscessus, can result in severe pulmonary infections. Current antibiotics confront significant challenges for treatment of these NTM infections due to emerging multidrug-resistance. Thus, development new targeted against agents is needed. We examined the inhibitory activities Ga(NO3)3, GaCl3, gallium meso-tetraphenylporphyrine (GaTP), nanoparticles (GaNP) intra- extracellular abscessus. GaTP, an analogue natural...

Mycobacterium tuberculosis is the leading cause of morbidity and death resulting from infectious disease worldwide. The incredible burden, combined with long course drug treatment an increasing incidence antimicrobial resistance among M. isolates, necessitates novel drugs targets for this deadly pathogen. Recent work has produced several promising clinical candidates targeting components electron transport chain (ETC) tuberculosis, highlighting pathway's potential as a target. Menaquinone...

Menaquinone is used for transporting electrons and essential the aerobic anaerobic respiratory systems of all pathogens prokaryotes. Many Gram-positive bacteria use only menaquinone in electron transport system. Thus, biosynthesis a potential target development inhibitors against including drug-resistant pathogens.After modeling, synthesis vitro testing, we determined that 7-methoxy-2-naphthol-based targeted MenA enzyme pathway. The developmental compounds 1 2 were active Mycobacterium...

Pseudomonas aeruginosa is a highly antibiotic-resistant opportunistic pathogenic bacteria that responsible for thousands of deaths each year. Infections with P. disproportionately impact individuals compromised immune systems as well cystic fibrosis patients, where lung infection leading cause morbidity and mortality. In previous work, we showed combination gallium (Ga) nitrate Ga protoporphyrin worked in several bacterial models but its mechanism action (MOA) unknown. the current have...

Abstract Menaquinone (MK) biosynthesis pathway is a potential target for evaluating antimicrobials in gram-positive bacteria. Here, 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA) was targeted to reduce methicillin-resistant Staphylococcus aureus (MRSA) growth. MenA inhibiting, long chain-based compounds were designed, synthesized and evaluated against MRSA menaquinone utilizing bacteria aerobic conditions. The results showed that these susceptible most of the compounds. (MK-4)...

There is a major need for the development of new therapeutics to combat antibiotic-resistant Staphylococcus aureus. Recently, gallium (Ga)-based complexes have shown promising antimicrobial effects against various bacteria, including multidrug-resistant organisms, by targeting multiple heme/iron-dependent metabolic pathways. Among these, Ga protoporphyrin (GaPP) inhibits bacterial growth heme pathways, aerobic respiration. Ga(NO3)3, an iron mimetic, disrupts elemental Here, we demonstrate...

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a global threat. The course of TB is negatively impacted coexistent infection with human immunodeficiency virus type 1 (HIV). Macrophage these pathogens modulates their production pro- and anti-inflammatory cytokines, which could play crucial role in pathogenesis. Despite the important macrophages containing variety microbes, both HIV M. tuberculosis infect replicate within cells during HIV-M. coinfection. Both require iron for...

The emergence of drug-resistant pathogens causes the greatest challenge for drug development research. Recently, gallium(III)-based compounds have received great attention as novel antimicrobial agents against pathogens. Here, we synthesized a new β-cyclodextrin Ga nanoparticle (CDGaTP) using tetraphenylporphyrin (GaTP, hemin analogue) and β-cyclodextrin. newly was nontoxic efficient at single dose, showing sustained release 15 days in vitro. CDGaTP's activity with transferrin or lactoferrin...

Protein chips are powerful tools as analytical and diagnostic devices for detection of biomolecular interactions, where the proteins covalently or noncovalently attached to biosensing surfaces capture detect target molecules biomarkers. Thus, fabrication regio- chemoselective immobilization biomolecules is a crucial step better biosensor performance. In our previous studies, strategy was demonstrated on glass surfaces. This now used regioselectively attach self-assembled monolayers (SAMs)...

The glyoxalase pathway (GP) is an antioxidant defense system that detoxifies metabolic byproduct methylglyoxal (MG). Through sequential reactions, reduced glutathione (GSH), I (glo-1), and II (glo-2) convert MG into d-lactate. Spontaneous reactions involving alter the structure function of cellular macromolecules through formation inflammatory advanced glycation endproducts (AGEs). Accumulation AGEs in neural cells contributes to oxidative stress (OS), a state elevated inflammation commonly...

Abstract Klebsiella pneumoniae (KLP) is a Gram‐negative pathogen that can be highly antibiotic‐resistant. Our group has worked with gallium‐based compounds as means of treating bacterial infections. Here the possible mechanism investigated for dual therapy comprised gallium nitrate (Ga(NO 3 ) and protoporphyrin (GaPP) on KLP. It found in vitro combination Ga(NO GaPP synergistic against The vivo efficacy additionally tested by pulmonary KLP infections mice. Much greater effectiveness are...

The biosynthetic pathways to isoprenoid compounds involve transfer of the prenyl moiety in allylic diphosphates electron-rich (nucleophilic) acceptors. acceptors can be many types nucleophiles, while only differ number isoprene units and stereochemistry double bonds hydrocarbon moieties. Because wide range nucleophilicities naturally occurring acceptors, mechanism for prenyltransfer reactions may dissociative or associative with early late transition states. We have measured δ-secondary...