Parasitic diarrheal disease: drug development and targets

Azam, Amir; Peerzada, Mudasir N.; Ahmad, Kamal

doi:10.3389/fmicb.2015.01183

Cited by 22 publications

(14 citation statements)

References 136 publications

(153 reference statements)

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“…This reduction step leads to the production of DNA-damaging compounds, which can kill the bacterium [58]. A further action mechanism of metronidazole may lead to production of nitroradical anions that reduce O 2 and thereby generate reactive oxygen species [59, 60]. Therefore, the contribution of HtrA to protection against oxidative stress is possible.…”

Section: Resultsmentioning

confidence: 99%

“…Puromycin causes the premature termination of protein synthesis in the translation process, which results in a large amount of misfolded proteins that can form toxic aggregates for cells [61, 62]. Metronidazole induces the production of DNA damaging radicals [74] and probably other reactive species that denature other cellular macromolecules are also formed [59, 60]. Other tested stresses such as osmotic, temperature, acid, basic and oxidative factors can result in protein denaturation and aggregation, which can lead to cell death.…”

Section: Discussionmentioning

confidence: 99%

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Chaperone activity of serine protease HtrA of Helicobacter pylori as a crucial survival factor under stress conditions

et al. 2019

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BackgroundSerine protease HtrA exhibits both proteolytic and chaperone activities, which are involved in cellular protein quality control. Moreover, HtrA is an important virulence factor in many pathogens including Helicobacter pylori, for which the crucial stage of infection is the cleavage of E-cadherin and other cell-to-cell junction proteins.MethodsThe in vitro study of H. pylori HtrA (HtrAHp) chaperone activity was carried out using light scattering assays and investigation of lysozyme protein aggregates. We produced H. pylori ∆htrA deletion and HtrAHp point mutants without proteolytic activity in strain N6 and investigated the survival of the bacteria under thermal, osmotic, acidic and general stress conditions as well as the presence of puromycin or metronidazole using serial dilution tests and disk diffusion method. The levels of cellular and secreted proteins were examined using biochemical fraction and Western blotting. We also studied the proteolytic activity of secreted HtrAHp using zymography and the enzymatic digestion of β-casein. Finally, the consequences of E-cadherin cleavage were determined by immunofluorescence microscopy.ResultsWe demonstrate that HtrAHp displays chaperone activity that inhibits the aggregation of lysozyme and is stable under various pH and temperature conditions. Next, we could show that N6 expressing only HtrA chaperone activity grow well under thermal, pH and osmotic stress conditions, and in the presence of puromycin or metronidazole. In contrast, in the absence of the entire htrA gene the bacterium was more sensitive to a number of stresses. Analysing the level of cellular and secreted proteins, we noted that H. pylori lacking the proteolytic activity of HtrA display reduced levels of secreted HtrA. Moreover, we compared the amounts of secreted HtrA from several clinical H. pylori strains and digestion of β-casein. We also demonstrated a significant effect of the HtrAHp variants during infection of human epithelial cells and for E-cadherin cleavage.ConclusionHere we identified the chaperone activity of the HtrAHp protein and have proven that this activity is important and sufficient for the survival of H. pylori under multiple stress conditions. We also pinpointed the importance of HtrAHp chaperone activity for E- cadherin degradation and therefore for the virulence of this eminent pathogen.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Chaperone activity of serine protease HtrA of Helicobacter pylori as a crucial survival factor under stress conditions

et al. 2019

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“…The integration of the PK and PD indices are critical in estimating the efficacy and potency of a given drug, hence, are the basis for the selection of an applicable drug and to optimize dosage formulation [ 28 ]. The PK/PD integration of cefquinome has been described previously in various animals [ 12 , 17 , 18 , 21 , 29 ]. In the present study, we investigated to optimize the dosage against strangles caused by Streptococcus equi subsp.…”

Section: Discussionmentioning

confidence: 99%

“…In order to bridge the gap, integration of PK parameters and multiple PD models, such as the maximum effect ( E max ) model, has been utilized to predict optimal dosages, which have been known to improve the clinical response to therapy and reduce the antimicrobial resistance [ 16 ]. Although studies regarding the integration of PK/PD of cefquinome have been conducted previously in some animals, there have been no previous attempts to suggest optimized dosage of cefquinome against S. equi in horses using PK/PD integration [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic integration for optimal dosage of cefquinome against Streptococcus equi subsp. equi in foals

Lee

Birhanu

Lee

et al. 2020

Vet Res

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Cefquinome is administered in horses for the treatment of respiratory infection caused by Streptococcus equi subsp. zooepidemicus, and septicemia caused by Escherichia coli. However, there have been no attempts to use cefquinome against Streptococcus equi subsp. equi (S. equi), the causative agent of strangles. Hence the objective of this study was to calculate an optimal dosage of cefquinome against S. equi based on pharmacokinetics and pharmacodynamics integration. Cefquinome (1.0 mg/kg) was administered by intravenous and intramuscular routes to six healthy thoroughbred foals. Serum cefquinome concentrations were determined by high-performance liquid chromatography. The in vitro and ex vivo antibacterial activity were determined from minimum inhibitory concentrations (MIC) and bacterial killing curves. The optimal dosage was calculated from the integration of pharmacokinetic parameters and area under the curve (AUC24h/MIC) values. Total body clearance and volume of distribution of cefquinome after intravenous administration were 0.06 L/h/kg and 0.09 L/kg, respectively. Following intramuscular administration, a maximum concentration of 0.73 μg/mL at 1.52 h (Tmax) and a systemic bioavailability of 37.45% were observed. The MIC of cefquinome against S. equi was 0.016 μg/mL. The ex vivo AUC24h/MIC values representing bacteriostatic, and bactericidal activity were 113.11, and 143.14 h, respectively. Whereas the %T > MIC for bactericidal activity was 153.34%. In conclusion, based on AUC24h/MIC values and pharmacokinetic parameters, cefquinome when administered by intramuscularly at a dosage of 0.53 mg/kg every 24 h, would be effective against infection caused by S. equi in foals. Further studies may be necessary to confirm its therapeutic efficacy in a clinical environment.

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“…Maximum effort should be directed towards new compounds to treat cryptosporidiosis because of the limited availability of effective drugs [70]. Maximum effort should be directed towards new compounds to treat cryptosporidiosis because of the limited availability of effective drugs [70].…”

Section: Development Of a Food-borne Parasitic Disease Vaccine And Nementioning

confidence: 99%

Food‐borne Parasitic Diseases in China

Bai

Zhou

Chen

et al. 2017

Food Safety in China

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9Food-borne parasitic diseases are human and animal diseases that are caused by helminths and protozoans, which are acquired through the consumption of infected or contaminated meat, fish, shellfish, molluscs, plants, water, reptiles, and amphibians. To date, 95 species of food-borne parasites have been identified; these parasites pose significant public health and socioeconomic problems [1]. The World Health Organization (WHO) focuses on food-borne parasitic diseases when conducting surveys to assess food-borne diseases. The organization has found that 7% of the world's food-borne diseases are caused by these parasites, which have become a major threat to human health and a public health problem. The infectious diseases caused by food-borne parasites are often referred to as neglected diseases, and from a food safety perspective, parasites have not received the same level of attention as other food-borne biological and chemical hazards. Nevertheless, they cause a high burden of disease in humans. The infections may have prolonged, severe, and sometimes fatal outcomes, resulting in considerable hardship in terms of food safety, security, quality of life, and negative impacts on livelihoods.In 2014, Food and Agriculture Organization of the United Nations (FAO) and WHO composed a list of 24 parasites ranked according to their "importance" and their primary food vehicle. Meanwhile, the FAO/ WHO defined global criteria for evaluating the 24 food-borne parasites and rated each parasite according to these criteria: (a) number of global illnesses, (b) global distribution, (c) morbidity -acute, (d) morbidity -chronic, (e) percentage chronic, (f ) mortality, (g) potential for increased burden, (h) trade relevance, and (i) socioeconomic impact. Finally, the top ten list was: Taenia solium (pork), Echinococcus granulosus (fresh produce), Echinococcus multilocularis (fresh produce), Toxoplasma gondii (meat from small ruminants, pork, beef, and game meat [red meat and organs]), Cryptosporidium spp. (fresh produce, fruit juice, and milk), Entamoeba histolytica (fresh produce), Trichinella spiralis (pork), Opisthorchiidae (freshwater fish), Ascaris spp. (fresh produce), and Trypanosoma cruzi (fruit juices).

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Parasitic diarrheal disease: drug development and targets

Cited by 22 publications

References 136 publications

Chaperone activity of serine protease HtrA of Helicobacter pylori as a crucial survival factor under stress conditions

Chaperone activity of serine protease HtrA of Helicobacter pylori as a crucial survival factor under stress conditions

Pharmacokinetic and pharmacodynamic integration for optimal dosage of cefquinome against Streptococcus equi subsp. equi in foals

Food‐borne Parasitic Diseases in China

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