scholarly journals Point Mutation in the Group B Streptococcal pbp2x Gene Conferring Decreased Susceptibility to β-Lactam Antibiotics

2008 ◽  
Vol 52 (8) ◽  
pp. 2915-2918 ◽  
Author(s):  
Samira Dahesh ◽  
Mary E. Hensler ◽  
Nina M. Van Sorge ◽  
Robert E. Gertz ◽  
Stephanie Schrag ◽  
...  
Keyword(s):  
Point Mutation ◽  
Wild Type ◽  
Beta Lactam ◽  
First Line ◽  
Group B Streptococci ◽  
Beta Lactam Antibiotics ◽  
Allelic Replacement ◽  
Group B

ABSTRACT Beta-lactam antibiotics (BLAs) are the first-line agents used against group B streptococci (GBS) infection. A clonal set of four independent, invasive GBS isolates with elevated MICs to BLAs were identified that shared a pbp2x mutation (Q557E) corresponding to a resistance-conferring pneumococcal mutation. BLA sensitivity was restored through allelic replacement or complementation with the wild-type pbp2x.

A randomized phase II multi-institutional trial of anlotinib plus docetaxel versus docetaxel in EGFR-wild-type non-small cell lung cancer (NSCLC) patients after progression on first-line platinum-base chemotherapy: ALTER-L018.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21703-e21703
Author(s):  
Lin Wu ◽  
Zhijun Wu ◽  
Zemin Xiao ◽  
Jie Weng ◽  
Zhongsha Ma ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Phase Iii ◽  
Wild Type ◽  
First Line ◽  
End Points ◽  
Phase Iii Trial ◽  
Platinum Based Chemotherapy ◽  
Group A ◽  
Group B ◽  
Nsclc Patients

e21703 Background: Anlotinib is an oral VEGFR, FGFR, PDGFR and c-Kit tyrosine kinase inhibitor, which can prolong both PFS and OS of refractory advanced NSCLC patients in phase III trial: ALTER0303. The combination of docetaxel and ramucirumab/nintedanib had been demonstrated activity in the second line therapy setting for NSCLC. We performed ALTER-L018 to assessed the safety and efficacy of anlotinib with docetaxel in EGFR-wild type refractory advanced NSCLC (NCT03624309). Methods: Patients (pts) with EGFR-wild type refractory advanced NSCLC, who failed to first-line platinum-based chemotherapy, were randomized to group A(anlotinib: 12mg QD from day 1 to 14 of a 21-day cycle +docetaxel: 75mg/m2 Q3W) and group B(docetaxel: 75mg/m2 Q3W). The primary end points is PFS, and secondary end points include OS, ORR, DCR and safety. Results: Between January and December 2019, 36 pts were enrolled at 10 institutions in Hunan China, with 31(15 in group A, 16 in group B) of these individuals being evaluable for treatment efficacy and safety. Pt characteristics(group A/ group B): median age: 55(39-70)/57(44-67); male: 73%/81%; non-squamous NSCLC: 86%/75%. Median PFS were 5.3 months (95%CI:2.76-7.85) in group A and 2.3 months (95%CI, 1.14-3.46) in group B (HR 0.42; 95% CI:0.16-1.13; p = 0.047); In group A and B, ORR and DCR were 26.67% versus 0%(p = 0.043), 60.00% versus 31.25%(p = 0.16), respectively. Among 31 pts, 89% of treatment-related AEs (TRAEs) were grade 1 or 2, and the most common TRAEs in group A were hand-foot syndrome, pruritus and insomnia of 13%(2/15) each; in group B were alopecia, constipation and anemia of 12%(1/16) each. Toxicities≥grade 3(TRAEs) included: neutropenia, leukopenia, diarrhea and hrombocytopenia, 6.6%(1/15) each in group A. There was 1 grade 5 AE in group A. Conclusions: This combination of anlotinib and docetaxel with significant difference PFS prolonging and manageable safety profile, is a viable option in relapsed NSCLC, should be considered following progression on platinum-based chemotherapy. It will be further explored in a randomized phase III trial. Clinical trial information: NCT03624309.

scholarly journals Phenotypic stress response of Pseudomonas aeruginosa following culture in water microcosms

2012 ◽  
Vol 10 (1) ◽  
pp. 130-139 ◽  
Author(s):  
Jihane Cheriaa ◽  
Mahmoud Rouabhia ◽  
Makaoui Maatallah ◽  
Amina Bakhrouf
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Environmental Changes ◽  
Starvation Period ◽  
Wild Type ◽  
Beta Lactam ◽  
Antibiotic Resistant ◽  
Aquatic Microcosms ◽  
Beta Lactam Antibiotics ◽  
In The Wild ◽  
Human Infections

The purpose of the present study was to explore the potential behavioural changes of Pseudomonas aeruginosa following growth in different aquatic environmental conditions. To achieve this, P. aeruginosa was cultured in various water microcosms for 12 months under fixed (pH, nutrients and temperature) factors. P. aeruginosa responses to these conditions were investigated using colony morphotype, biochemical and enzymatic characterisation, pyocin typing, serotyping, sensitivity to different classes of antibiotics and molecular identification. Results show that starvation in water microcosms lead to unusual phenotypes. Of interest is that the pyocin changed from 24/n in the wild type to 83/a following culture in the water microcosms, and the serotype changed from O6 in the wild type to O1 in microcosm-cultured P. aeruginosa. Furthermore, the starvation period in various aquatic microcosms enhanced the resistance of P. aeruginosa against beta-lactam antibiotics. Compared to the other aquatic environments, the seawater microcosm produced the greatest amount of variations in P. aeruginosa. Overall, data demonstrated a high adaptability of P. aeruginosa to environmental changes. This may explain the unusual antibiotic-resistant phenotypes belonging to P. aeruginosa species, and their capacity for spreading that leads to human infections.

scholarly journals Identification of Novel Adhesins from Group B Streptococci by Use of Phage Display Reveals that C5a Peptidase Mediates Fibronectin Binding

2002 ◽  
Vol 70 (6) ◽  
pp. 2869-2876 ◽  
Author(s):  
Christiane Beckmann ◽  
Joshua D. Waggoner ◽  
Theresa O. Harris ◽  
Glen S. Tamura ◽  
Craig E. Rubens
Keyword(s):  
Phage Display ◽  
Type Strain ◽  
Wild Type Strain ◽  
Host Cells ◽  
Dependent Manner ◽  
Wild Type ◽  
Chromosomal Dna ◽  
Group B Streptococci ◽  
A Genome ◽  
Group B

ABSTRACT Group B streptococci (GBS) are a major cause of pneumonia, sepsis, and meningitis in newborns and infants. GBS initiate infection of the lung by colonizing mucosal surfaces of the respiratory tract; adherence of the bacteria to host cells is presumed to be the initial step in and prerequisite for successful colonization (G. S. Tamura, J. M. Kuypers, S. Smith, H. Raff, and C. E. Rubens, Infect. Immun. 62:2450-2458, 1994). We have performed a genome-wide screen to identify novel genes of GBS that mediate adherence to fibronectin. A shotgun phage display library was constructed from chromosomal DNA of a serotype Ia GBS strain and affinity selected on immobilized fibronectin. DNA sequence analysis of different clones identified 19 genes with homology to known bacterial adhesin genes, virulence genes, genes involved in transport or metabolic processes, and genes with yet-unknown function. One of the isolated phagemid clones showed significant homology to the gene (scpB) for the GBS C5a peptidase, a surface-associated serine protease that specifically cleaves the complement component C5a, a chemotaxin for polymorphonuclear leukocytes. In this work we have demonstrated that affinity-purified recombinant ScpB and a peptide ScpB fragment (ScpB-PDF), similar to the peptide identified in the phagemid, bound fibronectin in a concentration-dependent manner. Adherence assays to fibronectin were performed, comparing an isogenic scpB mutant to the wild-type strain. Approximately 50% less binding was observed with the mutant than with the wild-type strain. The mutant phenotype could be fully restored by in trans complementation of the mutant with the cloned wild-type scpB gene, providing further evidence for the role of ScpB in fibronectin adherence. Our results suggest that C5a peptidase is a bifunctional protein, which enzymatically cleaves C5a and mediates adherence to fibronectin. Since binding of fibronectin has been implicated in attachment and invasion of eukaryotic cells by streptococci, our results may imply a second important role for this surface protein in the pathogenesis of GBS infections.

scholarly journals 85. Characterization of Group B streptococcus Strains with Reduced Susceptibility to Beta-lactam Antibiotics, Active Bacterial Core Surveillance, 1998–2017

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S173-S174
Author(s):  
Miwako Kobayashi ◽  
Lesley McGee ◽  
Sopio Chochua ◽  
Mirasol Apostol ◽  
Nisha B Alden ◽  
...  
Keyword(s):  
Group B Streptococcus ◽  
Age Groups ◽  
Clinical Information ◽  
Break Point ◽  
The United States ◽  
Beta Lactam ◽  
Beta Lactam Antibiotics ◽  
Young Infants ◽  
First Choice ◽  
Group B

Abstract Background In the United States, approximately 30,000 invasive group B Streptococcus (iGBS) infections occur annually; beta-lactam antibiotics (BL) are the first choice for prevention in young infants and treatment in all age groups. We obtained phenotypic and genotypic data for iGBS isolates from U.S. population-based surveillance sites to describe the emergence and characteristics of strains with reduced beta-lactam susceptibility (RS) over a 20-year period. Methods We analyzed RS iGBS isolates from eight Active Bacterial Core surveillance sites from 1998–2017. Through 2014, minimum inhibitory concentrations (MIC) for six BL were determined by broth microdilution, followed by whole genome sequencing (WGS) of RS isolates exceeding pre-defined breakpoints (Table 1). In 2015, WGS and MIC testing were performed for all isolates. After 2015, all isolates underwent WGS. MIC testing was continued on approximately 25% of isolates; otherwise, only those with modified penicillin binding protein (PBP) 2x transpeptidase amino acid sequence types or suboptimal WGS (< 1 % of isolates) underwent MIC testing. Clinical information on RS cases was abstracted from medical charts. Results Of 26,058 out of 27,269 iGBS isolates (95.6%) tested to date, 107 (0.4%) exhibited RS, increasing from 0% in 1998 to a peak of 1.1% in 2016 (P< 0.05 for trend) (Figure 1). Seven (6.5%) RS strains were from infants aged < 90 days; the rest were from adults aged ≥30 years (Table 2). RS strains consisted of 52 PBP2x types with diverse susceptibility patterns (Table 1). Seven RS strains (6.5%) had wild-type (non-modified) PBP2x; all met the RS criteria based on a single cephalosporin with a confirmed (repeated) MIC value at the break point (Table 1). Compared to non-RS strains, RS strains were more common in patients who presented with cellulitis and osteomyelitis and with underlying conditions such as diabetes or chronic skin breakdown (Table 2). Of 82 (85.4%) patients with RS strains and additional clinical information, 8.3% had known prior GBS infection; 26.8% had known BL exposure in the preceding year. Conclusion Preliminary results show that RS increased in recent years; strains RS to penicillin and ampicillin remain low. Variable pbp2x mutations have emerged and predominant strains have not yet been identified. Disclosures Nisha B. Alden, MPH, CDC (Grant/Research Support) Lee Harrison, MD, Dynavax (Consultant)GSK (Consultant)Merck (Consultant)OMVax (Consultant)Pfizer (Consultant)Sanofi Pasteur (Consultant)

scholarly journals Bacillus subtilis Regulators MntR and Zur Participate in Redox Cycling, Antibiotic Sensitivity, and Cell Wall Plasticity

2019 ◽  
Vol 202 (5) ◽  
Author(s):  
Paola Randazzo ◽  
Jamila Anba-Mondoloni ◽  
Anne Aubert-Frambourg ◽  
Alain Guillot ◽  
Christine Pechoux ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Wall ◽  
Bacillus Subtilis ◽  
Antibiotic Sensitivity ◽  
Transcriptional Regulators ◽  
Wild Type ◽  
Beta Lactam ◽  
Content Type ◽  
Cellular Processes ◽  
Beta Lactam Antibiotics

ABSTRACT The Bacillus subtilis MntR and Zur transcriptional regulators control homeostasis of manganese and zinc, two essential elements required in various cellular processes. In this work, we describe the global impact of mntR and zur deletions at the protein level. Using a comprehensive proteomic approach, we showed that 33 and 55 proteins are differentially abundant in ΔmntR and Δzur cells, respectively, including proteins involved in metal acquisition, translation, central metabolism, and cell wall homeostasis. In addition, both mutants showed modifications in intracellular metal ion pools, with significant Mg2+ accumulation in the ΔmntR mutant. Phenotypic and morphological analyses of ΔmntR and Δzur mutants revealed their high sensitivity to lysozyme, beta-lactam antibiotics, and external oxidative stress. Mutant strains had a modified cell wall thickness and accumulated lower levels of intracellular reactive oxygen species (ROS) than the wild-type strain. Remarkably, our results highlight an intimate connection between MntR, Zur, antibiotic sensitivity, and cell wall structure. IMPORTANCE Manganese and zinc are essential transition metals involved in many fundamental cellular processes, including protection against external oxidative stress. In Bacillus subtilis, Zur and MntR are key transcriptional regulators of zinc and manganese homeostasis, respectively. In this work, proteome analysis of B. subtilis wild-type, ΔmntR, and Δzur strains provided new insights into bacterial adaptation to deregulation of essential metal ions. Deletions of mntR and zur genes increased bacterial sensitivity to lysozyme, beta-lactam antibiotics, and external oxidative stress and impacted the cell wall thickness. Overall, these findings highlight that Zur and MntR regulatory networks are connected to antibiotic sensitivity and cell wall plasticity.

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