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.

Negatively charged nanodiscs for the reduction of toxicity and enhanced efficacy of polymyxin B against Acinetobacter baumannii sepsis.

The treatment of sepsis caused by multidrug-resistant (MDR) Gram-negative bacterial infections remains challenging. With these pathogens exhibiting resistance to carbapenems and new generation cephalosporins, the traditional antibiotic polymyxin B (PMB) has reemerged as a critical treatment option. However, its severe neurotoxicity and nephrotoxicity greatly limit the clinical application.

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.

Antibacterial Activity of an FtsZ Inhibitor Celastrol and Its Synergistic Effect with Vancomycin against Enterococci and .

Enterococci can cause various infectious diseases, including urinary tract infection, wound infection, and life-threatening endocarditis and meningitis. The emergence and transmission of vancomycin-resistant enterococci (VRE) have presented a challenge to clinical treatment. There is an urgent need to develop new strategies to fight against this pathogen.

ML364 exerts the broad-spectrum antivirulence effect by interfering with the bacterial quorum sensing system.

Antivirulence strategy has been developed as a nontraditional therapy which would engender a lower evolutionary pressure toward the development of antimicrobial resistance. However, the majority of the antivirulence agents currently in development could not meet clinical needs due to their narrow antibacterial spectrum and limited indications. Therefore, our main purpose is to develop broad-spectrum antivirulence agents that could target on both Gram-positive and Gram-negative pathogens.

Evaluation of Agar Dilution Method in Susceptibility Testing of Polymyxins for Enterobacteriaceae and Non-Fermentative Rods: Advantages Compared to Broth Microdilution and Broth Macrodilution.

An accurate and reliable susceptibility testing method for polymyxins is urgently needed not only for the clinical laboratory but also for new polymyxin-like lipopeptide development. Reference broth microdilution (rBMD), which was the recommended method by CLSI-EUCAST in clinics, has been proven not to be ideal, while the agar dilution (AD) method that was widely used in new antibiotics discovery has been neglected. In the present study, the AD method was compared with rBMD and broth macrodilution (BMAD) in susceptibility testing of polymyxin B and colistin against >200 Gram-negative isolates.

Synthesis and biological evaluation of novel N, N'-diarylurea derivatives as potent antibacterial agents against MRSA.

A series of new N, N'-diarylurea derivatives were designed and synthesized, some of which exhibited potent antibacterial activity against the drug-susceptible and drug-resistant Gram-positive strains. Especially, compounds 2c, 2g-2l showed broader antibacterial spectrum and more potent antibacterial activity (MIC = 0.30-2.

Effect of Different Tolerable Levels of Constitutive Expression on Escherichia coli.

To study the effect of different tolerable levels of constitutive expression on Escherichia coli, and to provide direct evidence for moderate resistance mediated by , construction of E. coli strains carrying on the chromosome with promoters of different strengths was conducted using λ-red recombination. Our results demonstrated that over-high expression of cannot be tolerated, and seven constructs with more than 200-fold transcriptional expression differences were obtained.

A Novel Tigecycline Adjuvant ML-7 Reverses the Susceptibility of Tigecycline-Resistant .

The increasing incidence of tigecycline resistance undoubtedly constitutes a serious threat to global public health. The combination therapies had become the indispensable strategy against this threat. Herein, 11 clinical tigecycline-resistant which mainly has mutations in , , or were collected for tigecycline adjuvant screening.

The discovery of 1, 3-diamino-7H-pyrrol[3, 2-f]quinazoline compounds as potent antimicrobial antifolates.

The shortage of new antibiotics makes infections caused by gram-negative (G) bacteria a significant clinical problem. The key enzymes involved in folate biosynthesis represent important targets for drug discovery, and new antifolates with novel mechanisms are urgently needed. By targeting to dihydrofolate reductase (DHFR), a series of 1,3-diamino-7H-pyrrol[3,2-f]quinazoline (PQZ) compounds were designed, and exhibited potent antibacterial activities in vitro, especially against multi-drug resistant G strains.

Strategies for Rapid Identification of Membrane Proteins and Polymyxin B's Effects.

, especially multidrug resistant , is a notable source of pressure in the areas of public health and antibiotic development. To overcome this problem, attention has been focused on membrane proteins. Different digestion methods and extraction detergents were examined for membrane proteome sample preparation, and label-free quantitative and targeted proteome analyses of the polymyxin B-induced ATCC 19606 membrane proteome were performed based on nano LC-MS/MS.

The Attenuated Protective Effect of Outer Membrane Vesicles Produced by a Positive Strain on Colistin Sensitive .

Resistance to colistin, especially mobilized colistin resistance (mcr), is a serious threat to public health since it may catalyze a return of the "pre-antibiotic era". Outer membrane vesicles (OMVs) play a role in antibiotic resistance in various ways. Currently, how OMVs participate in -mediated colistin resistance has not been established.

The combined antibacterial effects of sodium new houttuyfonate and berberine chloride against growing and persistent methicillin-resistant and vancomycin-intermediate Staphylococcus aureus.

Background: Infections caused by drug-resistant Staphylococcus aureus, especially vancomycin-intermediate Staphylococcus aureus (VISA), leave clinicians with limited therapeutic options for treatment. Persister cells is a leading cause of recalcitrant infection and antibiotic treatment failure, and there is no drug in clinical use that specifically targets persister cells currently. Here, we report a promising combination therapy of sodium new houttuyfonate (SNH) and berberine chloride (BBR) which is able to eradicate both growing and persistent drug-resistant Staphylococcus aureus.

Low Prevalence of Among Clinical Enterobacteriaceae Isolates and Co-transfer of and from Separate Donors.

and co-harboring isolates have been reported, usually reside on different plasmids, suggesting co-transfer possibility of the two genes from separate donors to the same recipient strain. This study aims at screening and characterization of carrying Enterobacteriaceae in Northern China, and studying the transfer ability of alone and in company with from a second donor. Three strains and one strain carrying gene were screened out from 1992 isolates in our study.

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.

Characterization of a hypervirulent multidrug-resistant ST23 Klebsiella pneumoniae carrying a bla IncFII plasmid and a pK2044-like plasmid.

Objective: To characterise a multidrug-resistant hypervirulent Klebsiella pneumoniae (MDR-hvKp) strain (Kpn1693) isolated from the sputum of a 67-year-old male patient diagnosed as having bronchiectasis with infection in Northern China.

Methods: Drug susceptibility testing was performed by broth microdilution method, and the hypervirulent phenotype of the strain was analysed by string test and a mice systemic infection model. The whole genome of Kpn1693 was sequenced using PacBio Sequel platform, de novo assembly was performed using SMRT Link v5.

and activity of d-serine in combination with -lactam antibiotics against methicillin-resistant .

As d-amino acids play important roles in the physiological metabolism of bacteria, combination of d-amino acids with antibiotics may provide synergistic antibacterial activity. The aim of the study was to evaluate and activity of d-serine alone and in combination with -lactams against methicillin-resistant (MRSA) strains, and to explore the possible sensitization mechanisms. The activity of d-serine, -lactams alone and in combinations was evaluated both by standard MICs, time-kill curves and checkerboard assays, and by murine systemic infection model as well as neutropenic thigh infection model.

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.

Synergistic Effect of Colistin Combined with PFK-158 against Colistin-Resistant Enterobacteriaceae.

As increasing numbers of colistin-resistant bacteria emerge, new therapies are urgently needed to treat infections caused by these pathogens. The discovery of new combination therapies is one important way to solve such problems. Here, we report that the antitumor drug PFK-158 and its analogs PFK-015 and 3PO can exert synergistic effects with colistin against colistin-resistant , including -positive or high-level-colistin-resistant (HLCR) isolates, as shown by a checkerboard assay.

Daphnetin: A Novel Anti- Agent.

Background: Antibiotic-resistant was increasingly found in infected individuals, which resulted in treatment failure and required alternative therapeutic strategies. Daphnetin, a coumarin-derivative compound, has multiple pharmacological activities.

Methods: The mechanism of daphnetin on was investigated focusing on its effect on cell morphologies, transcription of genes related to virulence, adhesion, and cytotoxicity to human gastric epithelial (GES-1) cell line.

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.