Higher levels of Pseudomonas aeruginosa LasB elastase expression are associated with early-stage infection in cystic fibrosis patients.

Pseudomonas aeruginosa is a common pathogen in cystic fibrosis (CF) patients and a major contributor to progressive lung damage. P. aeruginosa elastase (LasB), a key virulence factor, has been identified as a potential target for anti-virulence therapy.

Chemical Optimization of Selective LasB Elastase Inhibitors and Their Impact on LasB-Mediated Activation of IL-1β in Cellular and Animal Infection Models.

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.

Novel Specific Metallo-β-Lactamase Inhibitor ANT2681 Restores Meropenem Activity to Clinically Effective Levels against NDM-Positive .

The 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.

Role of D(T)PACE-based regimens as treatment of multiple myeloma with extramedullary relapse or refractory disease.

In multiple myeloma, atypical forms with extramedullary involvement exhibit poor survival. The poly-chemotherapeutic regimen D(T)-PACE has shown high activity in relapsed or refractory multiple myeloma. In this large monocentric retrospective study, we addressed the activity of D(T)-PACE-based regimens in 43 heavily pretreated patients with relapsed/refractory multiple myeloma and extramedullary disease.

Virtual Screening Approach to Identifying a Novel and Tractable Series of Elastase Inhibitors.

Novel 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.

Combination of brentuximab-vedotin and ifosfamide, carboplatin, etoposide in relapsed/refractory peripheral T-cell lymphoma.

Objectives: Relapsed/refractory peripheral T-cell lymphomas (PTCL) have a poor prognosis. We aimed at assessing efficacy of ifosfamide, carboplatin, etoposide (ICE) regimen, a known therapeutic option, to which we added brentuximab-vedotin (BV).

Methods: In this study, we retrospectively analyzed patients with PTCL treated with BV-ICE in our center between July 2014 and March 2018.

Discovery of , a Novel Broad-Spectrum Serine β-Lactamase Inhibitor of the Diazabicyclooctane Class, Which Strongly Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacterales and .

The 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.

ANT2681: SAR Studies Leading to the Identification of a Metallo-β-lactamase Inhibitor with Potential for Clinical Use in Combination with Meropenem for the Treatment of Infections Caused by NDM-Producing .

The 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.

SAR Studies Leading to the Identification of a Novel Series of Metallo-β-lactamase Inhibitors for the Treatment of Carbapenem-Resistant Enterobacteriaceae Infections That Display Efficacy in an Animal Infection Model.

The 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.

Discovery of a Novel Metallo-β-Lactamase Inhibitor That Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacteriaceae.

Infections 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.

[Obstetrical outcome after a cesarean section before 28 weeks of gestation - a case-control study].

Objectives: The aim of our study was to compare the mode of delivery after a caesarean performed before 28 weeks of gestation compared to a control group of patients who had a caesarean at term. Our secondary objective was to compare the risk of uterine rupture in these both groups.

Patients And Methods: This retrospective case-control was realised in a level III maternal center between the 1st of January 2001 and the 31th of December 2010.

[Placental abruption: Background and revisited pronostic factors about a series of 171 cases].

Objective: To describe the epidemiological, clinical and prognostic factors of placental abruption and fetal death in utero and to investigate possible risk factors for their occurrence.

Patients And Methods: Observational retrospective study including the women having presented a placental abruption between January 2001 and January 2012, in a IIB maternity. Women's sociodemographic characteristics, clinical symptoms and the method used to detect placental abruption were collected.

[Subsequent pregnancy outcomes after first pregnancy with severe preeclampsia and delivery before 34 weeks of gestation].

Objectives: Women who had severe preeclampsia are at high risk of gestational vascular complications (preeclampsia, gestational hypertension, fetal death, small for gestational age, placenta abruptio) in subsequent pregnancies. The aim of this study was to describe outcomes of subsequent pregnancy after severe preeclampsia with delivery before 34 weeks of gestation during the first pregnancy.

Patients And Methods: One hundred and thirty-four primiparous women delivered before 34 weeks of gestation resulting in severe preeclampsia between January 2002 and December 2009.

A common origin for the bacterial toxin-antitoxin systems parD and ccd, suggested by analyses of toxin/target and toxin/antitoxin interactions.

Bacterial toxin-antitoxin (TA) systems encode two proteins, a potent inhibitor of cell proliferation (toxin) and its specific antidote (antitoxin). Structural data has revealed striking similarities between the two model TA toxins CcdB, a DNA gyrase inhibitor encoded by the ccd system of plasmid F, and Kid, a site-specific endoribonuclease encoded by the parD system of plasmid R1. While a common structural fold seemed at odds with the two clearly different modes of action of these toxins, the possibility of functional crosstalk between the parD and ccd systems, which would further point to their common evolutionary origin, has not been documented.

[Prevention of early-onset group B Streptococcus infections. 2. Efficiency of the ANAES guidelines].

Objectives: To examine the efficiency on early-onset neonatal infections of the ANAES guidelines for early-onset infections prophylaxis, based on a systematic prenatal vaginal swab aiming Group B Streptococcus and/or infection risk factors during delivery.

Patients And Methods: This is a retrospective cohort study of early-onset infections during a period of 28 months (6125 deliveries) compared to an earlier period (6141 deliveries).

Results: The number of newborns admitted for suspected infection and the rate of sepsis have been unchanged.

[Prevention of early-onset group B Streptococcus infections. 1. Application of the ANAES guidelines].

Objectives: To examine adherence to the Anaes guidelines for early-onset infections prophylaxis, based on a systematic prenatal vaginal swab aiming group B Streptococcus and/or infection risk factors during delivery.

Patients And Methods: Retrospective study of 6125 consecutive deliveries through a 28-month period. Data were collected from the patients files recorded in a computer database.

parD toxin-antitoxin system of plasmid R1--basic contributions, biotechnological applications and relationships with closely-related toxin-antitoxin systems.

Toxin-antitoxin systems, as found in bacterial plasmids and their host chromosomes, play a role in the maintenance of genetic information, as well as in the response to stress. We describe the basic biology of the parD/kiskid toxin-antitoxin system of Escherichia coli plasmid R1, with an emphasis on regulation, toxin activity, potential applications in biotechnology and its relationships with related toxin-antitoxin systems. Special reference is given to the ccd toxin-antitoxin system of plasmid F because its toxin shares structural homology with the toxin of the parD system.

Generational coexistence and ancestor's inhibition in bacterial populations.

Generational coexistence in structured environments raises the possibility of a competition between ancestors and descendents. This type of kin competition, and in particular, the possibility that descendents might actively repress the ancestor's dominance, has been rarely considered in microbial evolutionary ecology. The recent discovery of the phenomenon of stationary-phase contact-dependent inhibition of bacterial ancestor cells by late descendents provides a new theoretical perspective to analyze intrapopulational evolutionary changes.

Novel Escherichia coli RF1 mutants with decreased translation termination activity and increased sensitivity to the cytotoxic effect of the bacterial toxins Kid and RelE.

Novel mutations in prfA, the gene for the polypeptide release factor RF1 of Escherichia coli, were isolated using a positive genetic screen based on the parD (kis, kid) toxin-antitoxin system. This original approach allowed the direct selection of mutants with altered translational termination efficiency at UAG codons. The isolated prfA mutants displayed a approximately 10-fold decrease in UAG termination efficiency with no significant changes in RF1 stability in vivo.

The evolution of contact-dependent inhibition in non-growing populations of Escherichia coli.

In the course of liquid culture, serial passage experiments with Escherichia coli K-12 bearing a mutator gene deletion (DeltamutS) we observed the evolution of strains that appeared to kill or inhibit the growth of the bacteria from where they were derived, their ancestors. We demonstrate that this inhibition occurs after the cells stop growing and requires physical contact between the evolved and ancestral bacteria. Thereby, it is referred to as stationary phase contact-dependent inhibition (SCDI).

Rho GTPase-activating bacterial toxins: from bacterial virulence regulation to eukaryotic cell biology.

Studies on the interactions of bacterial pathogens with their host have provided an invaluable source of information on the major functions of eukaryotic and prokaryotic cell biology. In addition, this expanding field of research, known as cellular microbiology, has revealed fascinating examples of trans-kingdom functional interplay. Bacterial factors actually exploit eukaryotic cell machineries using refined molecular strategies to promote invasion and proliferation within their host.

Interactions between the toxin Kid of the bacterial parD system and the antitoxins Kis and MazE.

The proteins Kid and Kis are the toxin and antitoxin, respectively, encoded by the parD operon of Escherichia coli plasmid R1. Kis prevents the inhibition of E. coli cell growth caused by the RNA cleavage activity of Kid.