scholarly journals Effect of Fluorescent Dyes onIn Vitro-Differentiated, Late-Stage Plasmodium falciparum Gametocytes

2014 ◽  
Vol 58 (12) ◽  
pp. 7398-7404 ◽  
Author(s):  
Tamirat Gebru ◽  
Benjamin Mordmüller ◽  
Jana Held
Keyword(s):  
Plasmodium Falciparum ◽  
Late Stage ◽  
Fluorescent Dyes ◽  
Clinical Symptoms ◽  
Laboratory Strain ◽  
Clinical Isolates ◽  
Synthetic Dyes ◽  
Content Type ◽  
Highly Active

ABSTRACTPlasmodium falciparumgametocytes are not associated with clinical symptoms, but they are responsible for transmitting the pathogen to mosquitoes. Therefore, gametocytocidal interventions are important for malaria control and resistance containment. Currently available drugs and vaccines are not well suited for that purpose. Several dyes have potent antimicrobial activity, but their use against gametocytes has not been investigated systematically. The gametocytocidal activity of nine synthetic dyes and four control compounds was tested against stage V gametocytes of the laboratory strain 3D7 and three clinical isolates ofP. falciparumwith a bioluminescence assay. Five of the fluorescent dyes had submicromolar 50% inhibitory concentration (IC50) values against mature gametocytes. Three mitochondrial dyes, MitoRed, dihexyloxacarbocyanine iodide (DiOC6), and rhodamine B, were highly active (IC50s < 200 nM). MitoRed showed the highest activity against gametocytes, with IC50s of 70 nM against 3D7 and 120 to 210 nM against clinical isolates. All compounds were more active against the laboratory strain 3D7 than against clinical isolates. In particular, the endoperoxides artesunate and dihydroartemisinin showed a 10-fold higher activity against 3D7 than against clinical isolates. In contrast to all clinically used antimalarials, several fluorescent dyes had surprisingly highin vitroactivity against late-stage gametocytes. Since they also act against asexual blood stages, they shall be considered starting points for the development of new antimalarial lead compounds.

scholarly journals In VitroActivity of Fluorescent Dyes against Asexual Blood Stages of Plasmodium falciparum

2012 ◽  
Vol 56 (11) ◽  
pp. 5982-5985 ◽  
Author(s):  
Fanny Joanny ◽  
Jana Held ◽  
Benjamin Mordmüller
Keyword(s):  
Plasmodium Falciparum ◽  
Fluorescent Dyes ◽  
New Drugs ◽  
Synthetic Dyes ◽  
Antimicrobial Drugs ◽  
Content Type ◽  
Starting Point ◽  
Drug Sensitivity Assay ◽  
Syto 9

ABSTRACTMany successful antimicrobial drugs originate from synthetic dyes. This paper reports thein vitroactivity of 14 fluorescent dyes againstPlasmodium falciparum. Five of these dyes (Hoechst 33342, MitoRed, DiOC6, SYTO 9, and rhodamine B) show activity at a low nanomolar concentration against twoP. falciparumstrains in the histidine-rich protein 2 drug sensitivity assay, while toxicity in HeLa cells is low. These dyes may be a starting point for developing new drugs againstP. falciparum.

scholarly journals Results from the China Antimicrobial Surveillance Network (CHINET) in 2017 of the In Vitro Activities of Ceftazidime-Avibactam and Ceftolozane-Tazobactam against Clinical Isolates of Enterobacteriaceae and Pseudomonas aeruginosa

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Dandan Yin ◽  
Shi Wu ◽  
Yang Yang ◽  
Qingyu Shi ◽  
Dong Dong ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Clinical Isolates ◽  
Surveillance Network ◽  
Content Type ◽  
Highly Active ◽  
Microdilution Method ◽  
Carbapenem Resistant ◽  
Antimicrobial Surveillance ◽  
Broth Microdilution Method

ABSTRACT The in vitro activities of ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C-T), and comparators were determined for 1,774 isolates of Enterobacteriaceae and 524 isolates of Pseudomonas aeruginosa collected by 30 medical centers from the China Antimicrobial Surveillance Network (CHINET) in 2017. Antimicrobial susceptibility testing was performed by the CLSI broth microdilution method, and blaKPC and blaNDM were detected by PCR for all carbapenem-resistant Enterobacteriaceae (CRE). Ceftazidime-avibactam demonstrated potent activity against almost all Enterobacteriaceae (94.6% susceptibility; MIC50, ≤0.25 mg/liter; MIC90, ≤0.25 to >32 mg/liter) and good activity against P. aeruginosa (86.5% susceptibility; MIC50/90, 2/16 mg/liter). Among the CRE, 50.8% (189/372 isolates) were positive for blaKPC-2, which mainly existed in ceftazidime-avibactam-susceptible Klebsiella pneumoniae isolates (92.1%, 174/189). Among the CRE, 17.7% (66/372 isolates) were positive for blaNDM, which mainly existed in strains resistant to ceftazidime-avibactam (71.7%, 66/92). Ceftolozane-tazobactam showed good in vitro activity against Escherichia coli and Proteus mirabilis (MIC50/90, ≤0.5/2 mg/liter; 90.5 and 93.8% susceptibility, respectively), and the rates of susceptibility of K. pneumoniae (MIC50/90, 2/>64 mg/liter) and P. aeruginosa (MIC50/90, 1/8 mg/liter) were 52.7% and 88.5%, respectively. Among the CRE strains, 28.6% of E. coli isolates and 85% of K. pneumoniae isolates were still susceptible to ceftazidime-avibactam, but only 7.1% and 1.9% of them, respectively, were susceptible to ceftolozane-tazobactam. The rates of susceptibility of the carbapenem-resistant P. aeruginosa isolates to ceftazidime-avibactam (65.7%) and ceftolozane-tazobactam (68%) were similar. Overall, both ceftazidime-avibactam and ceftolozane-tazobactam were highly active against clinical isolates of Enterobacteriaceae and P. aeruginosa recently collected across China, and ceftazidime-avibactam showed activity superior to that of ceftolozane-tazobactam against Enterobacteriaceae, whereas ceftolozane-tazobactam showed a better effect against P. aeruginosa.

scholarly journals Decreasingpfmdr1Copy Number Suggests that Plasmodium falciparum in Western Cambodia Is RegainingIn VitroSusceptibility to Mefloquine

2015 ◽  
Vol 59 (5) ◽  
pp. 2934-2937 ◽  
Author(s):  
Pharath Lim ◽  
Dalin Dek ◽  
Vorleak Try ◽  
Sokunthea Sreng ◽  
Seila Suon ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Combination Therapy ◽  
Molecular Marker ◽  
Copy Number ◽  
Artemisinin Combination Therapy ◽  
Clinical Isolates ◽  
Content Type

ABSTRACTDihydroartemisinin-piperaquine is the current frontline artemisinin combination therapy (ACT) forPlasmodium falciparummalaria in Cambodia but is now failing in several western provinces. To investigate artesunate plus mefloquine (AS+MQ) as a replacement ACT, we measured the prevalence of multiplepfmdr1copies—a molecular marker for MQ resistance—in 844P. falciparumclinical isolates collected in 2008 to 2013. Thepfmdr1copy number is decreasing in Western Cambodia, suggesting thatP. falciparumis regainingin vitrosusceptibility to MQ.

scholarly journals Gametocytes from K13 Propeller Mutant Plasmodium falciparum Clinical Isolates Demonstrate Reduced Susceptibility to Dihydroartemisinin in the Male Gamete Exflagellation Inhibition Assay

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
Sonia Lozano ◽  
Pablo Gamallo ◽  
Carolina González-Cortés ◽  
Jesús-Luís Presa Matilla ◽  
Rick M. Fairhurst ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Southeast Asia ◽  
Male Gamete ◽  
Clinical Isolates ◽  
Inhibition Assay ◽  
Wild Type ◽  
Content Type ◽  
Gamete Formation

ABSTRACT Mutations in the kelch propeller domain (K13 propeller) of Plasmodium falciparum parasites from Southeast Asia are associated with reduced susceptibility to artemisinin. We exposed in vitro-cultured stage V gametocytes from Cambodian K13 propeller mutant parasites to dihydroartemisinin and evaluated the inhibition of male gamete formation in an in vitro exflagellation inhibition assay (EIA). Gametocytes with the R539T and C580Y K13 propeller alleles were less susceptible to dihydroartemisinin and had significantly higher 50% inhibitory concentrations (IC50s) than did gametocytes with wild-type alleles.

scholarly journals In Vitro Activity of Cefepime-Zidebactam, Ceftazidime-Avibactam, and Other Comparators against Clinical Isolates of Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii: Results from China Antimicrobial Surveillance Network (CHINET) in 2018

2020 ◽  
Vol 65 (1) ◽  
pp. e01726-20
Author(s):  
Yang Yang ◽  
Yan Guo ◽  
Dandan Yin ◽  
Yonggui Zheng ◽  
Shi Wu ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acinetobacter Baumannii ◽  
Clinical Isolates ◽  
Surveillance Network ◽  
Gram Negative ◽  
Content Type ◽  
Highly Active ◽  
Carbapenem Resistant ◽  
Almost All

ABSTRACTThis study evaluated the in vitro activity of cefepime-zidebactam in comparison with that of ceftazidime-avibactam and other comparators against clinically significant Gram-negative bacillus isolates. A total of 3,400 nonduplicate Gram-negative clinical isolates were collected from 45 medical centers across China in the CHINET Program in 2018, including Enterobacterales (n = 2,228), Pseudomonas aeruginosa (n = 657), and Acinetobacter baumannii (n = 515). The activities of cefepime-zidebactam and 20 comparators were determined by broth microdilution as recommended by the Clinical and Laboratory Standards Institute. Cefepime-zidebactam demonstrated potent activity against almost all Enterobacterales (MIC50/90, 0.125/1 mg/liter) and good activity against P. aeruginosa (MIC50/90, 2/8 mg/liter). Among the 373 carbapenem-resistant Enterobacteriaceae isolates, 57.3% (213/373) and 15.3% (57/373) were positive for blaKPC-2 and blaNDM, respectively. Cefepime-zidebactam showed a MIC of ≤2 mg/liter for 92.0% (196/213) of blaKPC-2 producers and 79.7% (47/59) of blaNDM producers. Ceftazidime-avibactam showed good in vitro activity against Enterobacterales (MIC50/90, 0.25/2 mg/liter; 94.0% susceptible) and P. aeruginosa (MIC50/90, 4/16 mg/liter; 86.9% susceptible). Ceftazidime-avibactam was active against 9.1% of carbapenem-resistant Escherichia coli isolates (63.6% were blaNDM producers) and 84.6% of Klebsiella pneumoniae isolates (74.3% were blaKPC producers). Most (90.1%) blaKPC-2 producers were susceptible to ceftazidime-avibactam. Cefepime-zidebactam demonstrated limited activity (MIC50/90, 16/32 mg/liter) against the 515 A. baumannii isolates (79.2% were carbapenem resistant), and ceftazidime-avibactam was less active (MIC50/90, 64/>64 mg/liter). Cefepime-zidebactam was highly active against clinical isolates of Enterobacterales and P. aeruginosa, including blaKPC-2-positive Enterobacterales and blaNDM-positive Enterobacterales and carbapenem-resistant P. aeruginosa. And ceftazidime-avibactam was highly active against blaKPC-2-positive Enterobacterales and carbapenem-resistant P. aeruginosa.

scholarly journals In Vitro Activities of Piperaquine and Other 4-Aminoquinolines against Clinical Isolates of Plasmodium falciparum in Cameroon

2003 ◽  
Vol 47 (4) ◽  
pp. 1391-1394 ◽  
Author(s):  
Leonardo K. Basco ◽  
Pascal Ringwald
Keyword(s):  
Plasmodium Falciparum ◽  
Inhibitory Concentration ◽  
Geometric Mean ◽  
Central Africa ◽  
New Drugs ◽  
Clinical Isolates ◽  
Highly Active ◽  
Synthetic Drug ◽  
Further Development

ABSTRACT The spread of chloroquine-resistant Plasmodium falciparum calls for a constant search for new drugs. The in vitro activity of piperaquine, a new Chinese synthetic drug belonging to the bisquinolines, was evaluated in 103 fresh clinical isolates of P. falciparum in Cameroon, Central Africa, and compared with that of other 4-aminoquinoline and Mannich base derivatives and dihydroartemisinin. Piperaquine was highly active (geometric mean 50% inhibitory concentration, 38.9 nmol/liter; range, 7.76 to 78.3 nmol/liter) and equally active (P > 0.05) against the chloroquine-sensitive and the chloroquine-resistant isolates. There was a significant but low correlation of response between chloroquine and piperaquine (r = 0.257, P < 0.05). These results suggest that further development of piperaquine, in combination with dihydroartemisinin, holds promise for use in chloroquine-resistant regions of endemicity.

scholarly journals Repeat Polymorphisms in the Low-Complexity Regions of Plasmodium falciparum ABC Transporters and Associations withIn VitroAntimalarial Responses

2013 ◽  
Vol 57 (12) ◽  
pp. 6196-6204 ◽  
Author(s):  
John Okombo ◽  
Abdirahman I. Abdi ◽  
Steven M. Kiara ◽  
Leah Mwai ◽  
Lewa Pole ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Abc Transporters ◽  
Inhibitory Concentration ◽  
Low Complexity ◽  
Clinical Isolates ◽  
Inverse Association ◽  
Sequence Profile ◽  
Content Type ◽  
Functional Studies

ABSTRACTThePlasmodium falciparumgenome is rich in regions of low amino acid complexity which evolve with few constraints on size. To explore the extent of diversity in these loci, we sequenced repeat regions inpfmdr1,pfmdr5,pfmdr6,pfmrp2, and the antigenic locuspfmsp8in laboratory and cultured-adapted clinical isolates. We further assessed associations between the repeats and parasitein vitroresponses to 7 antimalarials to determine possible adaptive roles of these repeats in drug tolerance. Our results show extensive repeat variations in the reference and clinical isolates in all loci. We also observed a modest increase in dihydroartemisinin activity in parasites harboring thepfmdr1sequence profile 7-2-10 (reflecting the number of asparagine repeats, number of aspartate repeats, and number of asparagine repeats in the final series of the gene product) (P= 0.0321) and reduced sensitivity to chloroquine, mefloquine, quinine, and dihydroartemisinin in those with the 7-2-11 profile (P= 0.0051, 0.0068, 0.0011, and 0.0052, respectively). Interestingly, we noted an inverse association between two drugs whereby isolates with 6 asparagine repeats encoded bypfmdr6were significantly more susceptible to piperaquine than those with 8 (P= 0.0057). Against lumefantrine, those with 8 repeats were, however, more sensitive (P= 0.0144). Inpfmrp2, the 7-DNNNTS/NNNNTS (number of DNNNTS or NNNNTS motifs; underlining indicates dimorphism) repeat group was significantly associated with a higher lumefantrine 50% inhibitory concentration (IC50) (P= 0.008) than in those without. No associations were observed withpfmsp8. These results hint at the probable utility of some repeat conformations as markers ofin vitroantimalarial response; hence, biochemical functional studies to ascertain their role inP. falciparumare required.

scholarly journals Immune Characterization of Plasmodium falciparum Parasites with a Shared Genetic Signature in a Region of Decreasing Transmission

2014 ◽  
Vol 83 (1) ◽  
pp. 276-285 ◽  
Author(s):  
Amy K. Bei ◽  
Ababacar Diouf ◽  
Kazutoyo Miura ◽  
Daniel B. Larremore ◽  
Ulf Ribacke ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Clonal Diversity ◽  
Clinical Isolates ◽  
Immune Recognition ◽  
Content Type ◽  
Reverse Transcription Pcr ◽  
Genetic Signatures ◽  
Parasite Populations ◽  
Specific Parasite

As the intensity of malaria transmission has declined,Plasmodium falciparumparasite populations have displayed decreased clonal diversity resulting from the emergence of many parasites with common genetic signatures (CGS). We have monitored such CGS parasite clusters from 2006 to 2013 in Thiès, Senegal, using the molecular barcode. The first, and one of the largest observed clusters of CGS parasites, was present in 24% of clinical isolates in 2008, declined to 3.4% of clinical isolates in 2009, and then disappeared. To begin to explore the relationship between the immune responses of the population and the emergence and decline of specific parasite genotypes, we have determined whether antibodies to CGS parasites correlate with their prevalence. We measured (i) antibodies capable of inhibiting parasite growth in culture and (ii) antibodies recognizing the surfaces of infected erythrocytes (RBCs). IgG obtained from volunteers in 2009 showed increased reactivity to the surfaces of CGS-parasitized erythrocytes over IgG from 2008. SinceP. falciparumEMP-1 (PfEMP-1) is a major variant surface antigen, we usedvarUps quantitative reverse transcription-PCR (qRT-PCR) and sequencing with degenerate DBL1α domain primers to characterize thevargenes expressed by CGS parasites after short-termin vitroculture. CGS parasites show upregulation of UpsAvargenes and 2-cysteine-containing PfEMP-1 molecules and express the same dominantvartranscript. Our work indicates that the CGS parasites in this cluster express similarvargenes, more than would be expected by chance in the population, and that there is year-to-year variation in immune recognition of surface antigens on CGS parasite-infected erythrocytes. This study lays the groundwork for detailed investigations of the mechanisms driving the expansion or contraction of specific parasite clones in the population.

scholarly journals Novel Phage Lysin Capable of Killing the Multidrug-Resistant Gram-Negative Bacterium Acinetobacter baumannii in a Mouse Bacteremia Model

2015 ◽  
Vol 59 (4) ◽  
pp. 1983-1991 ◽  
Author(s):  
Rolf Lood ◽  
Benjamin Y. Winer ◽  
Adam J. Pelzek ◽  
Roberto Diez-Martinez ◽  
Mya Thandar ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Genomic Library ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Gram Negative ◽  
Content Type ◽  
Highly Active ◽  
Genes Encoding

ABSTRACTAcinetobacter baumannii, a Gram-negative multidrug-resistant (MDR) bacterium, is now recognized as one of the more common nosocomial pathogens. Because most clinical isolates are found to be multidrug resistant, alternative therapies need to be developed to control this pathogen. We constructed a bacteriophage genomic library based on prophages induced from 13A. baumanniistrains and screened it for genes encoding bacteriolytic activity. Using this approach, we identified 21 distinct lysins with different activities and sequence diversity that were capable of killingA. baumannii. The lysin (PlyF307) displaying the greatest activity was further characterized and was shown to efficiently kill (>5-log-unit decrease) all testedA. baumanniiclinical isolates. Treatment with PlyF307 was able to significantly reduce planktonic and biofilmA. baumanniibothin vitroandin vivo. Finally, PlyF307 rescued mice from lethalA. baumanniibacteremia and as such represents the first highly active therapeutic lysin specific for Gram-negative organisms in an array of native lysins found inAcinetobacterphage.

scholarly journals Comparative In Vitro Activities of Ceftaroline and Tedizolid against Clinical Strains of Staphylococcus aureus and Enterococcus: Results from the China Antimicrobial Surveillance Network (CHINET) in 2018

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Yan Guo ◽  
Yang Yang ◽  
Yonggui Zheng ◽  
Shi Wu ◽  
Dandan Yin ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Enterococcus Faecalis ◽  
Enterococcus Faecium ◽  
Clinical Usefulness ◽  
Clinical Isolates ◽  
Surveillance Network ◽  
Content Type ◽  
Highly Active ◽  
Antimicrobial Surveillance

ABSTRACT The in vitro activities of ceftaroline and tedizolid were compared against Staphylococcus aureus, Enterococcus faecalis, and Enterococcus faecium clinical isolates collected from the China Antimicrobial Surveillance Network. Ceftaroline demonstrated potent activity against S. aureus isolates (MIC50/90, ≤0.25/1 mg/liter). Tedizolid was also highly active against S. aureus (MIC50/90, 0.25/0.5 mg/liter) and Enterococcus (MIC50/90, 0.5/0.5 mg/liter) isolates. Our results support the clinical usefulness of ceftaroline and tedizolid in treating Gram-positive infections.

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