scholarly journals Recombinant ESAT-6-Like Proteins Provoke Protective Immune Responses against Invasive Staphylococcus aureus Disease in a Murine Model

2014 ◽  
Vol 83 (1) ◽  
pp. 339-345 ◽  
Author(s):  
Bao Zhong Zhang ◽  
Yan Hong Hua ◽  
Bin Yu ◽  
Candy Choi Yi Lau ◽  
Jian Piao Cai ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Responses ◽  
Survival Rates ◽  
Passive Immunization ◽  
Health Concern ◽  
Drug Resistant ◽  
Public Health Concern ◽  
Content Type ◽  
Resistant Strains ◽  
Drug Resistant Strains

Staphylococcus aureusis a common pathogen found in the community and in hospitals. Most notably, methicillin-resistantS. aureusis resistant to many antibiotics, which is a growing public health concern. The emergence of drug-resistant strains has prompted the search for alternative treatments, such as immunotherapeutic approaches. To date, most clinical trials of vaccines or of passive immunization againstS. aureushave ended in failure. In this study, we investigated two ESAT-6-like proteins secreted byS. aureus,S. aureusEsxA (SaEsxA) and SaEsxB, as possible targets for a vaccine. Mice vaccinated with these purified proteins elicited high titers of anti-SaEsxA and anti-SaEsxB antibodies, but these antibodies could not preventS. aureusinfection. On the other hand, recombinant SaEsxA (rSaEsxA) and rSaEsxB could induce Th1- and Th17-biased immune responses in mice. Mice immunized with rSaEsxA and rSaEsxB had significantly improved survival rates when challenged withS. aureuscompared with the controls. These findings indicate that SaEsxA and SaEsxB are two promising Th1 and Th17 candidate antigens which could be developed into multivalent and serotype-independent vaccines againstS. aureusinfection.

scholarly journals In Vitro Activity and MIC of Sitafloxacin against Multidrug-Resistant and Extensively Drug-Resistant Mycobacterium tuberculosis Isolated in Thailand

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Manoon Leechawengwongs ◽  
Therdsak Prammananan ◽  
Sarinya Jaitrong ◽  
Pamaree Billamas ◽  
Nampueng Makhao ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Critical Concentration ◽  
Multidrug Resistant ◽  
Quinolone Resistance ◽  
Drug Resistant ◽  
Content Type ◽  
Extensively Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains

ABSTRACT New fluoroquinolones (FQs) have been shown to be more active against drug-resistant Mycobacterium tuberculosis strains than early FQs, such as ofloxacin. Sitafloxacin (STFX) is a new fluoroquinolone with in vitro activity against a broad range of bacteria, including M. tuberculosis. This study aimed to determine the in vitro activity of STFX against all groups of drug-resistant strains, including multidrug-resistant M. tuberculosis (MDR M. tuberculosis), MDR M. tuberculosis with quinolone resistance (pre-XDR), and extensively drug-resistant (XDR) strains. A total of 374 drug-resistant M. tuberculosis strains were tested for drug susceptibility by the conventional proportion method, and 95 strains were randomly submitted for MIC determination using the microplate alamarBlue assay (MABA). The results revealed that all the drug-resistant strains were susceptible to STFX at a critical concentration of 2 μg/ml. Determination of the MIC90s of the strains showed different MIC levels; MDR M. tuberculosis strains had a MIC90 of 0.0625 μg/ml, whereas pre-XDR and XDR M. tuberculosis strains had identical MIC90s of 0.5 μg/ml. Common mutations within the quinolone resistance-determining region (QRDR) of gyrA and/or gyrB did not confer resistance to STFX, except that double mutations of GyrA at Ala90Val and Asp94Ala were found in strains with a MIC of 1.0 μg/ml. The results indicated that STFX had potent in vitro activity against all the groups of drug-resistant M. tuberculosis strains and should be considered a new repurposed drug for treatment of multidrug-resistant and extensively drug-resistant TB.

scholarly journals Sontochin as a Guide to the Development of Drugs against Chloroquine-Resistant Malaria

2012 ◽  
Vol 56 (7) ◽  
pp. 3475-3480 ◽  
Author(s):  
Sovitj Pou ◽  
Rolf W. Winter ◽  
Aaron Nilsen ◽  
Jane Xu Kelly ◽  
Yuexin Li ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Plasmodium Yoelii ◽  
Significant Activity ◽  
Drug Resistant ◽  
Content Type ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Derivatives Of

ABSTRACTSontochin was the original chloroquine replacement drug, arising from research by Hans Andersag 2 years after chloroquine (known as “resochin” at the time) had been shelved due to the mistaken perception that it was too toxic for human use. We were surprised to find that sontochin, i.e., 3-methyl-chloroquine, retains significant activity against chloroquine-resistant strains ofPlasmodium falciparum in vitro. We prepared derivatives of sontochin, “pharmachins,” with alkyl or aryl substituents at the 3 position and with alterations to the 4-position side chain to enhance activity against drug-resistant strains. Modified with an aryl substituent in the 3 position of the 7-chloro-quinoline ring, Pharmachin 203 (PH-203) exhibits low-nanomolar 50% inhibitory concentrations (IC50s) against drug-sensitive and multidrug-resistant strains andin vivoefficacy against patent infections ofPlasmodium yoeliiin mice that is superior to chloroquine. Our findings suggest that novel 3-position aryl pharmachin derivatives have the potential for use in treating drug resistant malaria.

scholarly journals Use of the NP-40 Detergent-Mediated Assay in Discovery of Inhibitors of β-Hematin Crystallization

2011 ◽  
Vol 55 (7) ◽  
pp. 3363-3369 ◽  
Author(s):  
Rebecca D. Sandlin ◽  
Melissa D. Carter ◽  
Patricia J. Lee ◽  
Jennifer M. Auschwitz ◽  
Susan E. Leed ◽  
...  
Keyword(s):  
Drug Target ◽  
Inhibitory Concentration ◽  
Protozoan Parasite ◽  
Drug Resistant ◽  
Digestive Vacuole ◽  
Content Type ◽  
Parasite Survival ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Important Drug

ABSTRACTThe protozoan parasite responsible for malaria affects over 500 million people each year. Current antimalarials have experienced decreased efficacy due to the development of drug-resistant strains ofPlasmodiumspp., resulting in a critical need for the discovery of new antimalarials. Hemozoin, a crystalline by-product of heme detoxification that is necessary for parasite survival, serves as an important drug target. The quinoline antimalarials, including amodiaquine and chloroquine, act by inhibiting the formation of hemozoin. The formation of this crystal does not occur spontaneously, and recent evidence suggests crystallization occurs in the presence of neutral lipid particles located in the acidic digestive vacuole of the parasite. To mimic these conditions, the lipophilic detergent NP-40 has previously been shown to successfully mediate the formation of β-hematin, synthetic hemozoin. Here, an NP-40 detergent-based assay was successfully adapted for use as a high-throughput screen to identify inhibitors of β-hematin formation. The resulting assay exhibited a favorableZ′ of 0.82 and maximal drift of less than 4%. The assay was used in a pilot screen of 38,400 diverse compounds at a screening concentration of 19.3 μM, resulting in the identification of 161 previously unreported β-hematin inhibitors. Of these, 48 also exhibited ≥90% inhibition of parasitemia in aPlasmodium falciparumwhole-cell assay at a screening concentration of 23 μM. Eight of these compounds were identified to have nanomolar 50% inhibitory concentration values near that of chloroquine in this assay.

scholarly journals MEDI4893* Promotes Survival and Extends the Antibiotic Treatment Window in a Staphylococcus aureus Immunocompromised Pneumonia Model

2015 ◽  
Vol 59 (8) ◽  
pp. 4526-4532 ◽  
Author(s):  
L. Hua ◽  
T. S. Cohen ◽  
Y. Shi ◽  
V. Datta ◽  
J. J. Hilliard ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Treatment ◽  
Adjunctive Therapy ◽  
Survival Rates ◽  
Passive Immunization ◽  
Bacterial Overgrowth ◽  
Content Type ◽  
Increased Risk ◽  
Immunocompromised Mice ◽  
Treatment Window

ABSTRACTImmunocompromised individuals are at increased risk ofStaphylococcus aureuspneumonia. Neutralization of alpha-toxin (AT) with the monoclonal antibody (MAb) MEDI4893* protects normal mice fromS. aureuspneumonia; however, the effects of the MAb in immunocompromised mice have not been reported. In this study, passive immunization with MEDI4893* increased survival rates and reduced bacterial numbers in the lungs in an immunocompromised murineS. aureuspneumonia model. Lungs from infected mice exhibited alveolar epithelial damage, protein leakage, and bacterial overgrowth, whereas lungs from mice passively immunized with MEDI4893* retained a healthy architecture, with an intact epithelial barrier. Adjunctive therapy or prophylaxis with a subtherapeutic MEDI4893* dose combined with subtherapeutic doses of vancomycin or linezolid improved survival rates, compared with the monotherapies. Furthermore, coadministration of MEDI4893* with vancomycin or linezolid extended the antibiotic treatment window. These data suggest that MAb-mediated neutralization of AT holds promise in strategies for prevention and adjunctive therapy among immunocompromised patients.

scholarly journals Accuracy of an amplicon-sequencing nanopore approach to identify variants in tuberculosis drug-resistance-associated genes

2021 ◽  
Vol 7 (12) ◽  
Author(s):  
Carla Mariner-Llicer ◽  
Galo A. Goig ◽  
Laura Zaragoza-Infante ◽  
Manuela Torres-Puente ◽  
Luis Villamayor ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Type Species ◽  
Variant Calling ◽  
Targeted Sequencing ◽  
Clinical Samples ◽  
Drug Resistant ◽  
Content Type ◽  
Link Type ◽  
Resistant Strains ◽  
Drug Resistant Strains

A rapid and accurate diagnostic assay represents an important means to detect Mycobacterium tuberculosis , identify drug-resistant strains and ensure treatment success. Currently employed techniques to diagnose drug-resistant tuberculosis include slow phenotypic tests or more rapid molecular assays that evaluate a limited range of drugs. Whole-genome-sequencing-based approaches can detect known drug-resistance-conferring mutations and novel variations; however, the dependence on growing samples in culture, and the associated delays in achieving results, represents a significant limitation. As an alternative, targeted sequencing strategies can be directly performed on clinical samples at high throughput. This study proposes a targeted sequencing assay to rapidly detect drug-resistant strains of M. tuberculosis using the Nanopore MinION sequencing platform. We designed a single-tube assay that targets nine genes associated with drug resistance to seven drugs and two phylogenetic-determining regions to determine strain lineage and tested it in nine clinical isolates and six sputa. The study’s main aim is to calibrate MinNION variant calling to detect drug-resistance-associated mutations with different frequencies to match the accuracy of Illumina (the current gold-standard sequencing technology) from both culture and sputum samples. After calibrating Nanopore MinION variant calling, we demonstrated 100% agreement between Illumina WGS and our MinION set up to detect known drug resistance and phylogenetic variants in our dataset. Importantly, other variants in the amplicons are also detected, decreasing the recall. We identify minority variants and insertions/deletions as crucial bioinformatics challenges to fully reproduce Illumina WGS results.

scholarly journals Role of Alanine Racemase Mutations in Mycobacterium tuberculosisd-Cycloserine Resistance

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Yoshio Nakatani ◽  
Helen K. Opel-Reading ◽  
Matthias Merker ◽  
Diana Machado ◽  
Sönke Andres ◽  
...  
Keyword(s):  
Alanine Racemase ◽  
Drug Resistant ◽  
Evolutionary Patterns ◽  
Content Type ◽  
Direct Measurements ◽  
Resistant Strains ◽  
Selection For ◽  
Drug Resistant Strains

ABSTRACT A screening of more than 1,500 drug-resistant strains of Mycobacterium tuberculosis revealed evolutionary patterns characteristic of positive selection for three alanine racemase (Alr) mutations. We investigated these mutations using molecular modeling, in vitro MIC testing, as well as direct measurements of enzymatic activity, which demonstrated that these mutations likely confer resistance to d-cycloserine.

scholarly journals Studies on the effects of 3-acetyl-4"-isovaleryltylosin against multiple-drug resistant strains of Staphylococcus aureus.

1981 ◽  
Vol 34 (3) ◽  
pp. 305-312 ◽  
Author(s):  
MASAMI TSUCHIYA ◽  
KAYOKO SUZUKAKE ◽  
MAKOTO HORI ◽  
TSUTOMU SAWA ◽  
TOMIO TAKEUCHI ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Multiple Drug ◽  
Drug Resistant ◽  
Multiple Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains

scholarly journals In VitroSusceptibility of Mycobacterium tuberculosis Isolates to an Oral Carbapenem Alone or in Combination with β-Lactamase Inhibitors

2014 ◽  
Vol 58 (11) ◽  
pp. 7010-7014 ◽  
Author(s):  
Yasuhiro Horita ◽  
Shinji Maeda ◽  
Yuko Kazumi ◽  
Norio Doi
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Human Blood ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Drug Resistant ◽  
Content Type ◽  
Extensively Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains

ABSTRACTWe evaluated the antituberculosis (anti-TB) activity of five β-lactams alone or in combination with β-lactamase inhibitors against 41 clinical isolates ofMycobacterium tuberculosis, including multidrug-resistant and extensively drug-resistant strains. Of those, tebipenem, an oral carbapenem, showed the most potent anti-TB activity against clinical isolates, with a MIC range of 0.125 to 8 μg/ml, which is achievable in the human blood. More importantly, in the presence of clavulanate, MIC values of tebipenem declined to 2 μg/ml or less.

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