LasB elastase is a broad-spectrum exoprotease and a key virulence factor of , a major pathogen causing lung damage and inflammation in acute and chronic respiratory infections. Here, we describe the chemical optimization of specific LasB inhibitors with druglike properties and investigate their impact in cellular and animal models of infection. Competitive inhibition of LasB was demonstrated through structural and kinetic studies.
View Article and Find Full Text PDFThe global dissemination of metallo-β-lactamase (MBL)-producing carbapenem-resistant (CRE) is a serious public health concern. Specifically, NDM (New Delhi MBL) has been a major cause of carbapenem therapy failures in recent years, particularly as effective treatments for serine-β-lactamase (SBL)-producing are now commercially available. Since the NDM gene is carried on promiscuous plasmids encoding multiple additional resistance determinants, a large proportion of NDM-CREs are also resistant to many commonly used antibiotics, resulting in limited and suboptimal treatment options.
View Article and Find Full Text PDFNovel therapies are required to treat chronic bacterial infections in cystic fibrosis (CF) sufferers. The most common pathogen responsible for these infections is , which persists within the lungs of CF sufferers despite intensive antibiotic treatment. elastase (also known as LasB or pseudolysin) is a key virulence determinant that contributes to the pathogenesis and persistence of infections in CF patients.
View Article and Find Full Text PDFThe diazabicyclooctanes (DBOs) are a class of serine β-lactamase (SBL) inhibitors that use a strained urea moiety as the warhead to react with the active serine residue in the active site of SBLs. The first in-class drug, avibactam, as well as several other recently approved DBOs (e.g.
View Article and Find Full Text PDFThe clinical effectiveness of the important β-lactam class of antibiotics is under threat by the emergence of resistance, mostly due to the production of acquired serine- (SBL) and metallo-β-lactamase (MBL) enzymes. To address this resistance issue, multiple β-lactam/β-lactamase inhibitor combinations have been successfully introduced into the clinic over the past several decades. However, all of those combinations contain SBL inhibitors and, as yet, there are no MBL inhibitors in clinical use.
View Article and Find Full Text PDFThe clinical effectiveness of carbapenem antibiotics such as meropenem is becoming increasingly compromised by the spread of both metallo-β-lactamase (MBL) and serine-β-lactamase (SBL) enzymes on mobile genetic elements, stimulating research to find new β-lactamase inhibitors to be used in conjunction with carbapenems and other β-lactam antibiotics. Herein, we describe our initial exploration of a novel chemical series of metallo-β-lactamase inhibitors, from concept to efficacy, in a survival model using an advanced tool compound (ANT431) in conjunction with meropenem.
View Article and Find Full Text PDFInfections caused by carbapenem-resistant (CRE) are increasingly prevalent and have become a major worldwide threat to human health. Carbapenem resistance is driven primarily by the acquisition of β-lactamase enzymes, which are able to degrade carbapenem antibiotics (hence termed carbapenemases) and result in high levels of resistance and treatment failure. Clinically relevant carbapenemases include both serine β-lactamases (SBLs; e.
View Article and Find Full Text PDFNew neprilysin inhibitors containing an α-mercaptoketone HSC(RR)CO group, as zinc ligand were designed. Two parameters were explored for potency optimization: the size of the inhibitor which could interact with the S, S' or S' domain of the enzyme and the nature of the substituents R, R of the mercaptoketone group. Introduction of a cyclohexyl chain in R, R position and a (3-thiophen)benzyl group in position R (compound 12n) yielded to the most potent inhibitor of this series with a Ki value of 2±0.
View Article and Find Full Text PDFStructure-activity studies were employed to investigate the stabilization of DNA-topoisomerases I and II covalent binary complexes by topopyrone analogues. The synthesis of five new topopyrone derivatives and study of their ability to stabilize DNA-topoisomerase I and DNA-topoisomerase II covalent binary complexes are described. The biochemical assays suggest that the orientation of the fused 1,4-pyrone ring and halogen substituents contribute importantly to the overall potency of the topopyrones as topoisomerase poisons.
View Article and Find Full Text PDFIntroduction: In the parathyroid gland, the calcium sensing receptor responds to small changes in circulating levels of Ca(2+), and consequently stimulates or inhibits the secretion of parathyroid hormone (PTH). Thus, ligands potentiating the action of calcium (calcimimetics) lead to decreased PTH secretion and can thus be useful for the treatment of hyperparathyroidism. On the other hand, ligands which antagonize the action of calcium (calcilytics) stimulate PTH secretion, favoring bone tissue regeneration.
View Article and Find Full Text PDFTwo series of cyclic nitrogen mustards structurally related to L-carnitine have been prepared. The cytotoxic activity of these compounds was evaluated by using Chlorambucil as a reference. In accordance with earlier report, the cytotoxicity is in direct correlation with the lipophilicity of the introduced alkyl chains.
View Article and Find Full Text PDFVerticipyrone has recently been isolated from the culture broth of Verticillium sp. and shown to inhibit NADH fumarate reductase, as well as NADH oxidoreductase (complex I) of the mitochondrial electron transport chain. In order to assess the structural elements in verticipyrone essential for complex I inhibitor, 15 structural analogues were prepared and analyzed for their effects on mitochondrial NADH oxidoreductase and NADH oxidase activities.
View Article and Find Full Text PDFThe cation-independent mannose 6-phosphate receptor (CI-M6PR) is essential for the endocytosis of proteins bearing the mannose 6-phosphate (M6P) recognition marker. This study described the synthesis of M6P and M6S analogs presenting greater affinity for CI-M6PR than their natural compounds. Moreover, the finding of their lack of cytotoxicity for human cells and of their increased stability in human serum supports the high potential of these isosteric derivatives in therapies requiring CI-M6PR targeting.
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