Small molecule inhibitors of the fosfomycin resistance enzyme FosM from Mycobacterium abscessus.

Fosfomycin is a safe broad-spectrum antibiotic that has not achieved widespread use because of the emergence of fosfomycin-modifying enzymes. Inhibition of fosfomycin-modifying enzymes could be used to help combat pathogens like Mycobacterium abscessus. Our previous work identified several inhibitors for the enzyme FosB from Staphylococcus aureus.

Discovery and development of novel substituted monohydrazides as potent antifungal agents.

Novel substituted monohydrazides synthesized for this study displayed broad-spectrum activity against various fungal strains, including a panel of clinically relevant strains. The activity of these compounds was either comparable or superior to amphotericin B against most of the fungal strains tested. These compounds possessed fungistatic activity in a time-kill assay and exhibited no mammalian cell toxicity.

Identification and analysis of small molecule inhibitors of FosB from .

Antimicrobial resistance (AMR) poses a significant threat to human health around the world. Though bacterial pathogens can develop resistance through a variety of mechanisms, one of the most prevalent is the production of antibiotic-modifying enzymes like FosB, a Mn-dependent l-cysteine or bacillithiol (BSH) transferase that inactivates the antibiotic fosfomycin. FosB enzymes are found in pathogens such as , one of the leading pathogens in deaths associated with AMR.

Aromatic hydrazides: A potential solution for Acinetobacter baumannii infections.

The emergence of multidrug-resistant bacteria and the poor efficacy of available antibiotics against these infections have led to the urgent need for novel antibiotics. Acinetobacter baumannii is one of high-priority pathogens due to its ability to mount resistance to different classes of antibiotics. In an effort to provide novel agents in the fight against infections caused by A.

Discovery and Mechanistic Analysis of Structurally Diverse Inhibitors of Acetyltransferase Eis among FDA-Approved Drugs.

Over one and a half million people die of tuberculosis (TB) each year. Multidrug-resistant TB infections are especially dangerous, and new drugs are needed to combat them. The high cost and complexity of drug development make repositioning of drugs that are already in clinical use for other indications a potentially time- and money-saving avenue.

Discovery of substituted benzyloxy-benzylamine inhibitors of acetyltransferase Eis and their anti-mycobacterial activity.

A clinically significant mechanism of tuberculosis resistance to the aminoglycoside kanamycin (KAN) is its acetylation catalyzed by upregulated Mycobacterium tuberculosis (Mtb) acetyltransferase Eis. In search for inhibitors of Eis, we discovered an inhibitor with a substituted benzyloxy-benzylamine scaffold. A structure-activity relationship study of 38 compounds in this structural family yielded highly potent (IC ∼ 1 μM) Eis inhibitors, which did not inhibit other acetyltransferases.

Discovery and Optimization of 6-(1-Substituted pyrrole-2-yl)--triazine Containing Compounds as Antibacterial Agents.

Antimicrobial drug resistance is a major health issue plaguing healthcare worldwide and leading to hundreds of thousands of deaths globally each year. Tackling this problem requires discovery and development of new antibacterial agents. In this study, we discovered novel 6-(1-substituted pyrrole-2-yl)--triazine containing compounds that potently inhibited the growth of regardless of its methicillin-resistant status, displaying minimum inhibitory concentration (MIC) values as low as 1 μM.

Structure-based design of haloperidol analogues as inhibitors of acetyltransferase Eis from to overcome kanamycin resistance.

Tuberculosis (TB), caused by (), is a deadly bacterial disease. Drug-resistant strains of make eradication of TB a daunting task. Overexpression of the enhanced intracellular survival (Eis) protein by confers resistance to the second-line antibiotic kanamycin (KAN).

Inhibition of Alginate Synthesis by Ebselen Oxide and Its Analogues.

is a Gram-negative opportunistic pathogen that is frequently found in the airways of cystic fibrosis (CF) patients due to the dehydrated mucus that collapses the underlying cilia and prevents mucociliary clearance. During this life-long chronic infection, cell accumulates mutations that lead to inactivation of the gene that results in the constitutive expression of operon and the production of alginate exopolysaccharide. The viscous alginate polysaccharide further occludes the airways of CF patients and serves as a protective matrix to shield from host immune cells and antibiotic therapy.

Development of Single-Stranded DNA Bisintercalating Inhibitors of Primase DnaG as Antibiotics.

Many essential enzymes in bacteria remain promising potential targets of antibacterial agents. In this study, we discovered that dequalinium, a topical antibacterial agent, is an inhibitor of Staphylococcus aureus primase DnaG (SaDnaG) with low-micromolar minimum inhibitory concentrations against several S. aureus strains, including methicillin-resistant bacteria.

Myeloid arginase-1 controls excessive inflammation and modulates T cell responses in Pseudomonas aeruginosa pneumonia.

Regulatory properties of macrophages associated with alternative activation serve to limit the exaggerated inflammatory response during pneumonia caused by Pseudomonas aeruginosa infection. Arginase-1 is an important effector of these macrophages believed to play an essential role in decreasing injury and promoting repair. We investigated the role of arginase-1 in the control of inflammatory immune responses to P.

Broad-Spectrum Antifungal Agents: Fluorinated Aryl- and Heteroaryl-Substituted Hydrazones.

Fluorinated aryl- and heteroaryl-substituted monohydrazones displayed excellent broad-spectrum activity against various fungal strains, including a panel of clinically relevant Candida auris strains relative to a control antifungal agent, voriconazole (VRC). These monohydrazones displayed less hemolysis of murine red blood cells than that of VRC at the same concentrations, possessed fungicidal activity in a time-kill study, and exhibited no mammalian cell cytotoxicity. In addition, these monohydrazones prevented the formation of biofilms that otherwise block antibiotic effectiveness and did not trigger the development of resistance when exposed to C.

Combining Chalcones with Donepezil to Inhibit Both Cholinesterases and Aβ Fibril Assembly.

The fact that the number of people with Alzheimer's disease is increasing, combined with the limited availability of drugs for its treatment, emphasize the need for the development of novel effective therapeutics for treating this brain disorder. Herein, we focus on generating 12 chalcone-donepezil hybrids, with the goal of simultaneously targeting amyloid-β (Aβ) peptides as well as cholinesterases (i.e.

Novel zafirlukast derivatives exhibit selective antibacterial activity against .

Periodontal disease is an oral chronic immune-inflammatory disease highly prevalent worldwide that is initiated by specific oral bacterial species leading to local and systemic effects. The development of new preventive/therapeutic strategies to specifically target oral periodontopathogens without perturbing oral microbiome species normally colonizing the oral cavity is needed. The fast and affordable strategy of repositioning of already FDA-approved drugs can be an answer to the development of novel treatments against periodontal pathogens such as .

Publisher Correction: Unusual substrate and halide versatility of phenolic halogenase PltM.

The original version of this Article contained an error in Fig. 1, in which the labels 'NADP' and 'NADPH + H' were incorrectly given as 'NADPH' and 'NADPH + H', respectively. This has been corrected in both the PDF and HTML versions of the Article.

Unusual substrate and halide versatility of phenolic halogenase PltM.

Controlled halogenation of chemically versatile substrates is difficult to achieve. Here we describe a unique flavin-dependent halogenase, PltM, which is capable of utilizing a wide range of halides for installation on a diverse array of phenolic compounds, including FDA-approved drugs and natural products, such as terbutaline, fenoterol, resveratrol, and catechin. Crystal structures of PltM in complex with phloroglucinol and FAD in different states yield insight into substrate recognition and the FAD recycling mechanism of this halogenase.

N,N'-diaryl-bishydrazones in a biphenyl platform: Broad spectrum antifungal agents.

N,N'-Diaryl-bishydrazones of [1,1'-biphenyl]-3,4'-dicarboxaldehyde, [1,1'-biphenyl]-4,4'-dicarboxaldehyde, and 4,4'-bisacetyl-1,1-biphenyl exhibited excellent antifungal activity against a broad spectrum of filamentous and non-filamentous fungi. These N,N'-diaryl-bishydrazones displayed no antibacterial activity in contrast to previously reported N,N'-diamidino-bishydrazones and N-amidino-N'-aryl-bishydrazones. The leading candidate, 4,4'-bis((E)-1-(2-(4-fluorophenyl)hydrazono)ethyl)-1,1'-biphenyl, displayed less hemolysis of murine red blood cells at concentrations at or below that of a control antifungal agent (voriconazole), was fungistatic in a time-kill study, and possessed no mammalian cytotoxicity and no toxicity with respect to hERG inhibition.

Differential Effects of Linkers on the Activity of Amphiphilic Tobramycin Antifungals.

As the threat associated with fungal infections continues to rise and the availability of antifungal drugs remains a concern, it becomes obvious that the need to bolster the antifungal armamentarium is urgent. Building from our previous findings of tobramycin (TOB) derivatives with antifungal activity, we further investigate the effects of various linkers on the biological activity of these aminoglycosides. Herein, we analyze how thioether, sulfone, triazole, amide, and ether functionalities affect the antifungal activity of alkylated TOB derivatives against 22 , , and species.

Comprehensive review of chemical strategies for the preparation of new aminoglycosides and their biological activities.

A systematic analysis of all synthetic and chemoenzymatic methodologies for the preparation of aminoglycosides for a variety of applications (therapeutic and agricultural) reported in the scientific literature up to 2017 is presented. This comprehensive analysis of derivatization/generation of novel aminoglycosides and their conjugates is divided based on the types of modifications used to make the new derivatives. Both the chemical strategies utilized and the biological results observed are covered.

Novel fluconazole derivatives with promising antifungal activity.

The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activity of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents.

Alkylated Piperazines and Piperazine-Azole Hybrids as Antifungal Agents.

The extensive use of fluconazole (FLC) and other azole drugs has caused the emergence and rise of azole-resistant fungi. The fungistatic nature of FLC in combination with toxicity concerns have resulted in an increased demand for new azole antifungal agents. Herein, we report the synthesis and antifungal activity of novel alkylated piperazines and alkylated piperazine-azole hybrids, their time-kill studies, their hemolytic activity against murine erythrocytes, as well as their cytotoxicity against mammalian cells.

New Application of Neomycin B-Bisbenzimidazole Hybrids as Antifungal Agents.

Alkylated aminoglycosides and bisbenzimidazoles have previously been shown to individually display antifungal activity. Herein, we explore for the first time the antifungal activity (in liquid cultures and in biofilms) of ten alkylated aminoglycosides covalently linked to either mono- or bisbenzimidazoles. We also investigate their toxicity against mammalian cells, their hemolytic activity, and their potential mechanism(s) of action (inhibition of fungal ergosterol biosynthetic pathway and/or reactive oxygen species (ROS) production).

Synthesis and investigation of novel benzimidazole derivatives as antifungal agents.

The rise and emergence of resistance to antifungal drugs by diverse pathogenic fungal strains have resulted in an increase in demand for new antifungal agents. Various heterocyclic scaffolds with different mechanisms of action against fungi have been investigated in the past. Herein, we report the synthesis and antifungal activities of 18 alkylated mono-, bis-, and trisbenzimidazole derivatives, their toxicities against mammalian cells, as well as their ability to induce reactive oxygen species (ROS) in yeast cells.

A review of patents (2011-2015) towards combating resistance to and toxicity of aminoglycosides.

Since the discovery of the first aminoglycoside (AG), streptomycin, in 1943, these broad-spectrum antibiotics have been extensively used for the treatment of Gram-negative and Gram-positive bacterial infections. The inherent toxicity (ototoxicity and nephrotoxicity) associated with their long-term use as well as the emergence of resistant bacterial strains have limited their usage. Structural modifications of AGs by AG-modifying enzymes, reduced target affinity caused by ribosomal modification, and decrease in their cellular concentration by efflux pumps have resulted in resistance towards AGs.