Characterizing the pharmacological interaction of the antimalarial combination artefenomel-piperaquine in healthy volunteers with induced blood-stage Plasmodium falciparum to predict efficacy in patients with malaria.

Background: The combination antimalarial artefenomel-piperaquine failed to achieve target efficacy in a phase 2b study in Africa and Vietnam. We retrospectively evaluated whether characterizing the pharmacological interaction of this antimalarial combination in a volunteer infection study (VIS) would have enabled prediction of the phase 2b study results.

Methods: Twenty-four healthy adults enrolled over three consecutive cohorts were inoculated with Plasmodium falciparum-infected erythrocytes on day 0.

Characterising the blood-stage antimalarial activity of pyronaridine in healthy volunteers experimentally infected with Plasmodium falciparum.

With the spread of artemisinin resistance throughout Southeast Asia and now in Africa, the antimalarial drug pyronaridine is likely to become an increasingly important component of new antimalarial drug regimens. However, the antimalarial activity of pyronaridine in humans has not been completely characterised. This volunteer infection study aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) relationship of pyronaridine in malaria naïve adults.

Characterizing the Blood-Stage Antimalarial Activity of Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum.

Background: The long-acting 8-aminoquinoline tafenoquine may be a good candidate for mass drug administration if it exhibits sufficient blood-stage antimalarial activity at doses low enough to be tolerated by glucose 6-phosphate dehydrogenase (G6PD)-deficient individuals.

Methods: Healthy adults with normal levels of G6PD were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Different single oral doses of tafenoquine were administered on day 8.

Transmission Blocking Activity of Low-dose Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum.

Background: Blocking the transmission of parasites from humans to mosquitoes is a key component of malaria control. Tafenoquine exhibits activity against all stages of the malaria parasite and may have utility as a transmission blocking agent. We aimed to characterize the transmission blocking activity of low-dose tafenoquine.

Spermidine biosynthesis and transport modulate pneumococcal autolysis.

Polyamines are small cationic molecules that have far-reaching roles in biology. In the case of pathogenic bacteria, these functions include those central to their pathogenesis. Streptococcus pneumoniae is a major bacterial pathogen, causing a diverse range of diseases that account for significant morbidity and mortality worldwide.

Site of isolation determines biofilm formation and virulence phenotypes of Streptococcus pneumoniae serotype 3 clinical isolates.

Streptococcus pneumoniae is a diverse species causing invasive as well as localized infections that result in massive global morbidity and mortality. Strains vary markedly in pathogenic potential, but the molecular basis is obscured by the diversity and plasticity of the pneumococcal genome. In the present study, S.

Interplay between manganese and iron in pneumococcal pathogenesis: role of the orphan response regulator RitR.

Streptococcus pneumoniae (the pneumococcus) is a major human pathogen that is carried asymptomatically in the nasopharynx by up to 70% of the human population. Translocation of the bacteria into internal sites can cause a range of diseases, such as pneumonia, otitis media, meningitis, and bacteremia. This transition from nasopharynx to growth at systemic sites means that the pneumococcus needs to adjust to a variety of environmental conditions, including transition metal ion availability.

Streptococcus pneumoniae uses glutathione to defend against oxidative stress and metal ion toxicity.

The thiol-containing tripeptide glutathione is an important cellular constituent of many eukaryotic and prokaryotic cells. In addition to its disulfide reductase activity, glutathione is known to protect cells from many forms of physiological stress. This report represents the first investigation into the role of glutathione in the Gram-positive pathogen Streptococcus pneumoniae.

Phenotypic characterization of a copA mutant of Neisseria gonorrhoeae identifies a link between copper and nitrosative stress.

NGO0579 is annotated copA in the Neisseria gonorrhoeae chromosome, suggesting that it encodes a cation-transporting ATPase specific for copper ions. Compared to wild-type cells, a copA mutant was more sensitive to killing by copper ions but not to other transition metals. The mutant also accumulated a greater amount of copper, consistent with the predicted role of CopA as a copper efflux pump.

LuxS mediates iron-dependent biofilm formation, competence, and fratricide in Streptococcus pneumoniae.

During infection, Streptococcus pneumoniae exists mainly in sessile biofilms rather than in planktonic form, except during sepsis. The capacity to form biofilms is believed to be important for nasopharyngeal colonization as well as disease pathogenesis, but relatively little is known about the regulation of this process. Here, we investigated the effect of exogenous iron [Fe(III)] as well as the role of luxS (encoding S-ribosylhomocysteine lyase) on biofilm formation by S.

Novel bacterial MerR-like regulators their role in the response to carbonyl and nitrosative stress.

Recognition of the diversity of transcriptional regulators of the MerR family has increased considerably over the last decade and it has been established that not all MerR-like regulators are involved in metal ion recognition. A new type of MerR-like regulator was identified in Neisseria gonorrhoeae that is distinct from metal-binding MerR proteins. This novel transcription factor, the Neisseria merR-like regulator (NmlR) is related to a large and diverse group of MerR-like regulators.

The MerR/NmlR family transcription factor of Streptococcus pneumoniae responds to carbonyl stress and modulates hydrogen peroxide production.

The NmlR(sp) transcription factor of Streptococcus pneumoniae is shown to induce adhC (alcohol dehydrogenase) expression in the presence of both formaldehyde and methylglyoxal. nmlR(sp) and adhC mutant strains display altered and opposite aerobic growth phenotypes. The nmlR(sp) strain exhibits increased resistance to high oxygen tension, attributable to decreased H(2)O(2) production, which correlated with downregulation of carbamoyl phosphate synthase (carB).

Esterase D is essential for protection of Neisseria gonorrhoeae against nitrosative stress and for bacterial growth during interaction with cervical epithelial cells.

estD encodes a carboxylic ester hydrolase and is part of the NmlR regulon in Neisseria gonorrhoeae. An estD mutant was found to be susceptible to nitrite and to S-nitrosoglutathione. This mutant was also unable to infect and survive within human cervical epithelial cells, and it showed reduced ability to form a biofilm on these cells.

Thioredoxin reductase is essential for protection of Neisseria gonorrhoeae against killing by nitric oxide and for bacterial growth during interaction with cervical epithelial cells.

In Neisseria gonorrhoeae, the MerR family transcription factor NmlR activates 3 operons in response to disulfide stress. In the present study, we show that trxB, a monocistronic operon under the control of NmlR, encodes a functional thioredoxin reductase. It is shown that neisserial TrxB has biochemical properties similar to those of its homologue from Escherichia coli.

Evidence for distinctive mechanisms of S-nitrosoglutathione metabolism by AdhC in two closely related species, Neisseria gonorrhoeae and Neisseria meningitidis.

The adhC gene from 11 strains of Neisseria gonorrhoeae was distinguished from its homologue in Neisseria meningitidis by the presence of a premature stop codon caused by a single base insertion. Mutational analysis showed that NADH S-nitrosoglutathione oxidoreductase activity was associated with adhC in Neisseria meningitidis but not in Neisseria gonorrhoeae.

NmlR of Neisseria gonorrhoeae: a novel redox responsive transcription factor from the MerR family.

A MerR-like regulator (NmlR -Neisseria merR-like Regulator) identified in the Neisseria gonorrhoeae genome lacks the conserved cysteines known to bind metal ions in characterized proteins of this family. Phylogenetic analysis indicates that NmlR defines a subfamily of MerR-like transcription factors with a distinctive pattern of conserved cysteines within their primary structure. NmlR regulates itself and three other genes in N.

Survey of ferroxidase expression and siderophore production in clinical isolates of Pseudomonas aeruginosa.

Ferroxidase (encoded by the mco gene), a component of a ferrous iron uptake pathway in Pseudomonas aeruginosa, was detected in all of the 35 respiratory clinical isolates surveyed; in contrast, considerable variation in siderophore expression was observed. The ubiquitous expression of this periplasmic ferroxidase suggests that it plays a key role in iron uptake in this opportunistic pathogen.