The antibacterial activity of 1,2,3-triazole- and 1,2,4-triazole-containing hybrids against Staphylococcus aureus: An updated review (2020-present)

: Staphylococcus aureus (S. aureus), a prominent, highly contagious nosocomial and community-acquired bacterial pathogen, can cause a broad spectrum of diseases. Antibiotic-resistant S. aureus strains, which pose potential causes of morbidity and mortality, have continuously emerged in recent years, calling for novel anti-S. aureus agents. 1,2,3-Triazole and 1,2,4-triazole, the bioisostere of amides, esters, and carboxylic acids, are potent inhibitors of DNA gyrase, topoisomerase IV, efflux pumps, filamentous temperature-sensitive protein Z, and penicillin-binding protein. In particular, 1,2,3-triazole- and 1,2,4-triazole-containing hybrids have the potential to exert dual or multiple antibacterial mechanisms of action. Moreover, 1,2,3-triazole-cephalosporin hybrid cefatrizine, 1,2,3-triazole-oxazolidinone hybrid radezolid, and 1,2,4-triazolo[1,5-a]pyrimidine hybrid essramycin, have already been used in clinical practice to treat bacterial infections. Hence, 1,2,3-triazole- and 1,2,4-triazole-containing hybrids possess promising broad-spectrum antibacterial activity against diverse clinically significant organisms, including drug-resistant forms. This review is an update on the latest development of 1,2,3-triazole- and 1,2,4-triazole-containing hybrids with anti-S. aureus activity, covering articles published between January 2020 and July 2021.

Cryo-EM structure of the dimeric Rhodobacter sphaeroides RC-LH1 core complex at 2.9 Å: the structural basis for dimerisation

The dimeric reaction centre light-harvesting 1 (RC-LH1) core complex of Rhodobacter sphaeroides converts absorbed light energy to a charge separation, and then it reduces a quinone electron and proton acceptor to a quinol. The angle between the two monomers imposes a bent configuration on the dimer complex, which exerts a major influence on the curvature of the membrane vesicles, known as chromatophores, where the light-driven photosynthetic reactions take place. To investigate the dimerisation interface between two RC-LH1 monomers, we determined the cryogenic electron microscopy structure of the dimeric complex at 2.9 Å resolution. The structure shows that each monomer consists of a central RC partly enclosed by a 14-subunit LH1 ring held in an open state by PufX and protein-Y polypeptides, thus enabling quinones to enter and leave the complex. Two monomers are brought together through N-terminal interactions between PufX polypeptides on the cytoplasmic side of the complex, augmented by two novel transmembrane polypeptides, designated protein-Z, that bind to the outer faces of the two central LH1 β polypeptides. The precise fit at the dimer interface, enabled by PufX and protein-Z, by C-terminal interactions between opposing LH1 αβ subunits, and by a series of interactions with a bound sulfoquinovosyl diacylglycerol lipid, bring together each monomer creating an S-shaped array of 28 bacteriochlorophylls. The seamless join between the two sets of LH1 bacteriochlorophylls provides a path for excitation energy absorbed by one half of the complex to migrate across the dimer interface to the other half.

Therapeutic Perspectives in Sneddon’s Syndrome

Sneddon’s syndrome is a rare but severe progressive chronic disease, characterized by multiple discoloration skin patches called Livedo racemosa and recurrent cerebrovascular events. It mainly affects women aged around 40. Considering the two main forms, antiphospholipid (APS) positive and negative, the available treatments are directed at either one of them. The idiopathic form (APS negative) is associated with a more severe prognosis as chronic oral anticoagulant therapy (COA) is more difficult to manage. One therapeutic perspective in controlling disease progression in these patients is by understanding the protein Z deficiency in these patients as a deciding factor in the success of the COA therapy.

Proteomic analysis reveals some common proteins in the kidney stone matrix

Background Proteins are the most abundant component of kidney stone matrices and their presence may reflect the process of the stone’s formation. Many studies have explored the proteomics of urinary stones and crystals. We sought to comprehensively identify the proteins found in kidney stones and to identify new, reliable biomolecules for use in nephrolithiasis research. Methods We conducted bioinformatics research in November 2020 on the proteomics of urinary stones and crystals. We used the ClusterProfiler R package to transform proteins into their corresponding genes and Ensembl IDs. In each study we located where proteomic results intersected to determine the 20 most frequently identified stone matrix proteins. We used the Human Protein Atlas to obtain the biological information of the 20 proteins and conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) analysis to explore their biological functions. We also performed immunohistochemistry to detect the expression of the top five stone matrix proteins in renal tissue. Results We included 19 relevant studies for analysis. We then identified 1,409 proteins in the stone matrix after the duplicates were removed. The 20 most-commonly identified stone matrix proteins were: S100A8, S100A9, uromodulin, albumin, osteopontin, lactotransferrin, vitamin K-dependent protein Z, prothrombin, hemoglobin subunit beta, myeloperoxidase, mannan-binding lectin serine protease 2, lysozyme C, complement C3, serum amyloid P-component, cathepsin G, vitronectin, apolipoprotein A-1, eosinophil cationic protein, fibrinogen alpha chain, and apolipoprotein D. GO and KEGG analysis revealed that these proteins were typically engaged in inflammation and immune response.Immunohistochemistry of the top five stone matrix proteins in renal tissue showed that the expression of S100A8, S100A9, and osteopontin increased, while uromodulin decreased in kidney stone patients. Albumin was rarely expressed in the kidney with no significant difference between healthy controls and kidney stone patients. Conclusion Proteomic analysis revealed some common inflammation-related proteins in the kidney stone matrix. The role of these proteins in stone formation should be explored for their potential use as diagnostic biomarkers and therapeutic targets for urolithiasis.

The proteolytic inactivation of protein Z-dependent protease inhibitor by neutrophil elastase might promote the procoagulant activity of NETs

Septic shock is the archetypal clinical setting in which extensive cross talk between inflammation and coagulation dysregulates the latter. The main anticoagulant systems are systematically impaired, depleted and/or downregulated. Protein Z-dependent protease inhibitor (ZPI) is an anticoagulant serpin that not only targets coagulation factors Xa and XIa but also acts as an acute phase reactant whose plasma concentration rises in inflammatory settings. The objective of the present study was to assess the plasma ZPI antigen level in a cohort of patients suffering from septic shock with or without overt-disseminated intravascular coagulation (DIC). The plasma ZPI antigen level was approximately 2.5-fold higher in the patient group (n=100; 38 with DIC and 62 without) than in healthy controls (n=31). The elevation’s magnitude did not appear to depend on the presence/absence of DIC. Furthermore, Western blots revealed the presence of cleaved ZPI in plasma from patients with severe sepsis, independently of the DIC status. In vitro, ZPI was proteolytically inactivated by purified neutrophil elastase (NE) and by NE on the surface of neutrophil extracellular traps (NETs). The electrophoretic pattern of ZPI after NE-catalyzed proteolysis was very similar to that resulting from the clotting process - suggesting that the cleaved ZPI observed in severe sepsis plasma is devoid of anticoagulant activity. Taken as a whole, our results (i) suggest that NE is involved in ZPI inactivation during sepsis, and (ii) reveal a novel putative mechanism for the procoagulant activity of NETs in immunothrombosis.