In vivo pharmacodynamic study of the novel polymyxin MRX-8.

In previous studies, polymyxin MRX-8 demonstrated potent in vitro antibacterial activity with a reduced nephrotoxicity risk and an improved PK/PD profile compared with polymyxin B. In this study, the in vivo antibacterial efficacy of intravenously administered MRX-8 was evaluated in murine models of systemic infection (induced by intraperitoneal injection), lung infection (induced by intratracheal route inoculation), and ascending urinary tract infection (induced by intraurethral inoculation) with P. aeruginosa, K.

High level non-carbapenemase carbapenem resistance by overlaying mutations of , and in .

Unlabelled: Carbapenem-resistant (CRPA) is a global threat, but the mechanism of non-carbapenemase carbapenem resistance is still unclear. In the current study, we investigated the contributions of point mutations in , , and to carbapenem resistance in during evolution studies with consecutive clinical isolates. Real-time qPCR and Electrophoretic Mobility Shift Assay demonstrated that MexR (Gln55Pro) mutation increased MexAB efflux pump genes expression by altering MexR's binding capacity, leading to a four- to eight-fold increase in meropenem MIC in the Pae d1 Green ∆ and PAO1∆ mutants.

In vivo pharmacodynamic study of contezolid acefosamil, a prodrug of contezolid for oral and intravenous administration.

Objectives: Contezolid acefosamil is a novel O-acyl phosphoramidate prodrug of contezolid. In the current study, we aimed to systemically evaluate the efficacy of contezolid acefosamil against infections caused by multiple Gram-positive pathogens, and compare the efficacy of the prodrug by oral and intravenous administrations.

Methods: The in vivo pharmacodynamic efficacy of contezolid acefosamil was evaluated in mouse models of systemic (with five S.

Beilunmycin, a new virginiamycins antibiotic from mangrove-derived sp. 2BBP-J2 and the antibacterial activity by inhibiting protein translation.

One new virginiamycin derivative, 'beilunmycin' (), and three known virginiamycin antibiotics, 16-hydroxy-virginiamycin M1 (), virginiamycin M2 (), and virginiamycin M1 (), were isolated from the culture of a mangrove-derived endophytic sp. 2BBP-J2. The structures were characterized on the basis of their spectroscopic data, and the absolute configuration of was established by ECD calculations.

Clinical and microbiological characteristics of hypervirulent Klebsiella pneumoniae (hvKp) in a hospital from North China.

Introduction: The clinical and molecular characteristics of hypervirulent Klebsiella pneumoniae (hvKp) in various provinces of China have been reported, however, there have been few reports in Hebei Province, North China.

Methodology: The hvKp was identified by PCR amplification of hypervirulence-related genes, the hypermucoviscous phenotype was determined by the "string test", the drug susceptibility analysis was performed using the VITEK® 2 Compact Bacterial Identification and Monitoring System. Logistic regression was used to identify risk factors for hvKp infection.

Design, Synthesis, and Bioactivity of Cyclic Lipopeptide Antibiotics with Varied Polarity, Hydrophobicity, and Positive Charge Distribution.

Twenty-three polymyxin analogs with variations at nine amino acid positions were synthesized and assessed for antimicrobial activity and renal cytotoxicity. Compounds , , , and (MIC = 0.125-4 μg/mL) had similar or stronger activities against susceptible and drug-resistant strains of , , , and compared to polymyxin B (MIC = 1-2 μg/mL).

Design, synthesis, and biological activity evaluation of a series of pleuromutilin derivatives with novel C14 side chains.

In this work, according to the 'me-too me-better' design strategy, a peculiar side chain different from lefamulin at C14 position of pleuromutilin was introduced. A series of novel thioether pleuromutilin derivatives containing cyclohexane in the C14 chain was synthesized by ten-step synthesis reaction. All derivatives were characterized by Nuclear Magnetic Resonance (NMR) and High Resolution Mass Spectrometer (HRMS).

Synthesis and antibacterial evaluation against resistant Gram-negative bacteria of monobactams bearing various substituents on oxime residue.

Based on the structural characteristics of aztreonam (AZN) and its target PBP3, a series of new monobactam derivatives bearing various substituents on oxime residue were prepared and evaluated for their antibacterial activities against susceptible and resistant Gram-negative bacteria. Among them, compounds 8p and 8r displayed moderate potency with MIC values of 0.125-32 μg/mL against most tested Gram-negative strains, comparable to AZN.

Microdialysis combined with liquid chromatography-tandem mass spectrometry for the quantitation of gemifloxacin and its application to a muscle penetration study in healthy and MRSA-infected rats.

Pharmacological efficacy is based on the drug concentration in target tissues, which usually cannot be represented by the plasma concentration. The purpose of this study was to compare the pharmacokinetic characteristics of gemifloxacin in plasma and skeletal muscle and evaluate its tissue penetration in both healthy and MRSA (methicillin-resistant Staphylococcus aureus)-infected rats. A microdialysis (MD) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to determine free gemifloxacin concentrations in rat plasma and skeletal muscle simultaneously.

Synthesis and biological evaluation of 7-substituted cycloberberine derivatives as potent antibacterial agents against MRSA.

A series of new 7-substituted cycloberberine (CBBR) derivatives were synthesized and evaluated for their antibacterial activities against Gram-positive pathogens, taking CBBR as the lead. The SAR revealed that the introduction of a substituent at the C7 position resulted in a potency against both the reference Gram-positive bacteria and MDR clinical isolates, much higher than that of CBBR. Compound 1f with a 7-phenyl group exhibited higher activities against MRSA and VRE than that of vancomycin, with MIC values of 1-8 μg/mL.

Isolation, Structure Elucidation, and Total Synthesis of Myrtuspirone A from Myrtus communis.

A pair of enantiomeric triketone-phloroglucinol hybrids, (+)- and (-)-myrtuspirone A (1), featuring an unprecedented 3-isopropyl-3 H-spiro[benzofuran-2,1'-cyclohexane] backbone, were isolated from the leaves of Myrtus communis. The absolute configuration of each enantiomer of 1 was determined by X-ray diffraction and chemical calculations. Furthermore, the gram-scale total syntheses of (±)-1 and (-)-1 were conducted in four steps using a Michael- N-iodosuccinimide (NIS)-mediated (3 + 2)-annulation reaction.

Synthesis and Biological Evaluation of Quinoline Derivatives as a Novel Class of Broad-Spectrum Antibacterial Agents.

Nineteen new quinoline derivatives were prepared via the Mannich reaction and evaluated for their antibacterial activities against both Gram-positive (G⁺) and Gram-negative (G) bacteria, taking compound as the lead. Among the target compounds, quinolone coupled hybrid exerted the potential effect against most of the tested G⁺ and G strains with MIC values of 0.125⁻8 μg/mL, much better than those of .

Design, synthesis, and bioevaluation of a novel class of (E)-4-oxo-crotonamide derivatives as potent antituberculosis agents.

A series of novel (E)-4-oxo-2-crotonamide derivatives were designed and synthesized to find potent antituberculosis agents. All the target compounds were evaluated for their in vitro activity against Mycobacterium tuberculosis HRv(MTB). Results reveal that 4-phenyl moiety at part A and short methyl group at part C were found to be favorable.

Structure analysis of transposons carrying the aac(6')-aph(2″) gene in Enterococcus faecalis isolated in Beijing, China, and comparison of their transfer efficiency.

Transfer of aac(6')-aph(2″) transposons mediating high-level gentamicin resistance (HLGR) in Enterococcus faecalis is a serious problem in the clinic. However, factors affecting the transfer of aac(6')-aph(2″) have not yet been elucidated. The current study aimed to examine the genetic and molecular basis of HLGR in E.

Synthesis and antibacterial evaluation of 13-substituted cycloberberine derivatives as a novel class of anti-MRSA agents.

A series of new 13-substituted cycloberberine (CBBR) derivatives were prepared and evaluated for their antibacterial activities against Gram-positive bacteria taking CBBR as the lead. Structure-activity relationship revealed that the introduction of a suitable electron-donating group at the 13-position in CBBR might be beneficial for the antibacterial potency. Among them, compounds 5b and 5w exhibited high potency against methicillin-sensitive (MSSA) and resistant strains of S.

Catalytic asymmetric total syntheses of myrtucommuacetalone, myrtucommuacetalone B, and callistrilones A, C, D and E.

Herein, we describe a concise catalytic approach to the first asymmetric total syntheses of myrtucommuacetalone, myrtucommuacetalone B, and callistrilones A, C, D and E. The syntheses proceed in only 5-7 steps from the readily available compound , without the need for protecting groups. Key features of the syntheses include a unique organocatalytic asymmetric Friedel-Crafts-type Michael addition with high enantioselectivity and a broad substrate scope, a novel Michael-ketalization-annulation cascade reaction, and an oxidative [3 + 2] cycloaddition.

Synthesis and Bioactivity Investigation of the Individual Components of Cyclic Lipopeptide Antibiotics.

In this paper, 26 natural polymyxin components and a new derivative S were synthesized, and their differences in efficacy and toxicity have been investigated. Almost all of the synthesized components showed strong activity against both susceptible and resistant strains of E. coli, K.

Recombinant expression and biochemical characterization of Mycobacterium tuberculosis 3Fe-4S ferredoxin Rv1786.

Ferredoxins are iron-sulfur protein that mediate electron transfer in cytochrome P450 mono-oxygenase (CYP)-related catalytic reactions in a wide variety of organisms. Rv1786 is a putative ferredoxin, encoded by a gene located downstream of the gene encoding CYP143A1 in the Mycobacterium tuberculosis genome. However, the structure and function of Rv1786 have remained unclear.

D-chiro-inositol effectively attenuates cholestasis in bile duct ligated rats by improving bile acid secretion and attenuating oxidative stress.

Cholestatic liver diseases are important causes of liver cirrhosis and liver transplantation, but few drugs are available for treatment. D-chiro-inositol (DCI), an isomer of inositol found in many Leguminosae plants and in animal viscera, is used clinically for the treatment of polycystic ovary syndrome (PCOS) and diabetes mellitus. In this study, we investigated whether DCI exerted an anti-cholestatic effect and its underlying mechanisms.

A novel protein kinase inhibitor IMB-YH-8 with anti-tuberculosis activity.

Protein kinase B (PknB) is one of the Mycobacterium tuberculosis serine/threonine protein kinases and has an essential role in sustaining mycobacterial growth. Here, we identified and characterized a novel small molecule compound named IMB-YH-8 that inhibited PknB and served as anti-mycobacteria lead compound. IMB-YH-8 inhibited PknB auto-phosphorylation and the phosphorylation of GarA by PknB in a dose-dependent manner.

Berberine-induced bioactive metabolites of the gut microbiota improve energy metabolism.

Objective: Berberine (BBR) clinically lowers blood lipid and glucose levels via multi-target mechanisms. One of the possible mechanisms is related to its effect on the short chain fatty acids (SCFAs) of the gut microbiota. The goal of this study is to investigate the therapeutic effect and mode of action of BBR working through SCFAs of the gut microbiota (especially, butyrate).

Damxungmacin A and B, Two New Amicoumacins with Rare Heterocyclic Cores Isolated from Bacillus subtilis XZ-7.

Two new amicoumacins, named Damxungmacin A () and B (), were isolated from the culture broth of a soil-derived bacterium XZ-7. Their chemical structures were elucidated by spectroscopic studies (UV, IR, NMR and HR-ESI-MS). Compound possessed a 1,4-diazabicyclo[2.