Evaluating New Compounds to Treat Burkholderia pseudomallei Infections

Ross, Brittany N.; Myers, Julia N.; Muruato, Laura A.; Tapia, Daniel; Torres, Alfredo G.

doi:10.3389/fcimb.2018.00210

Cited by 30 publications

(28 citation statements)

References 34 publications

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“…MIC of 2–6 μg/ml for common B . pseudomallei isolates [ 38 – 40 ]). We evaluated the effectiveness of our assays using the Z’ statistic [ 34 ], commonly used for high-throughput screening (HTS) [ 41 ].…”

Section: Resultsmentioning

confidence: 99%

“…We aimed to develop an assay that would identify compounds that reduced the proportion of B. thailandensis cells that remained viable when delivered in combination with ceftazidime (730 μM; 400 μg/ml; this is equivalent to the peak blood concentration given for melioidosis septicemia; c.f. MIC of 2-6 μg/ml for common B. pseudomallei isolates [38][39][40]). We evaluated the effectiveness of our assays using the Z' statistic [34], commonly used for high-throughput screening (HTS) [41].…”

Section: Assay Developmentmentioning

confidence: 99%

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Drug screening to identify compounds to act as co-therapies for the treatment of Burkholderia species

et al. 2021

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Burkholderia pseudomallei is a soil-dwelling organism present throughout the tropics. It is the causative agent of melioidosis, a disease that is believed to kill 89,000 people per year. It is naturally resistant to many antibiotics, requiring at least two weeks of intravenous treatment with ceftazidime, imipenem or meropenem followed by 6 months of orally delivered co-trimoxazole. This places a large treatment burden on the predominantly middle-income nations where the majority of disease occurs. We have established a high-throughput assay for compounds that could be used as a co-therapy to potentiate the effect of ceftazidime, using the related non-pathogenic bacterium Burkholderia thailandensis as a surrogate. Optimization of the assay gave a Z’ factor of 0.68. We screened a library of 61,250 compounds and identified 29 compounds with a pIC50 (-log10(IC50)) greater than five. Detailed investigation allowed us to down select to six “best in class” compounds, which included the licensed drug chloroxine. Co-treatment of B. thailandensis with ceftazidime and chloroxine reduced culturable cell numbers by two orders of magnitude over 48 hours, compared to treatment with ceftazidime alone. Hit expansion around chloroxine was performed using commercially available compounds. Minor modifications to the structure abolished activity, suggesting that chloroxine likely acts against a specific target. Finally, an initial study demonstrates the utility of chloroxine to act as a co-therapy to potentiate the effect of ceftazidime against B. pseudomallei. This approach successfully identified potential co-therapies for a recalcitrant Gram-negative bacterial species. Our assay could be used more widely to aid in chemotherapy to treat infections caused by these bacteria.

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Section: Resultsmentioning

confidence: 99%

Section: Assay Developmentmentioning

confidence: 99%

Drug screening to identify compounds to act as co-therapies for the treatment of Burkholderia species

et al. 2021

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“…Compound 2 (IC 50 of 2.38 µM) is thought to be a DNA groove binder as likely mechanism of action, and is active against several bacterial and fungal pathogens [42]. Besides, this compound was among the seven MMV Pathogen Box compounds that exhibited bacteriostatic or bactericidal activity against Burkholderia pseudomallei , the causative agent of melioidosis, a disease that requires long-term treatment regimens with no assurance of bacterial clearance [43]. To a lesser extent, compound 3 also exhibited promising activity against E. histolytica (IC 50 5.63µM).…”

Section: Discussionmentioning

confidence: 99%

Screening the MMV Open Access Pathogen box unveils novel and potent inhibitors of Amoebiasis agent: Entamoeba histolytica

Toghueo

Dize

Laleu

et al. 2019

Preprint

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21Amoebiasis caused by the protozoan parasite Entamoeba histolytica remains a major public health 22 hazard, as being the second cause of death among parasitic infections. Although currently 23 prescribed drugs have shown to be effective in the treatment of amoebiasis, side effects and 24 emergence of parasites resistance prompted the search for novel drug to control this disease. In 25 this regard, the Medicines for Malaria Venture (MMV) Pathogen Box library of selected 26 compounds was screened to identify anti-Entamoeba histolytica agents using the resazurin based 27 fluorescence assay. Overall, the results revealed three novel anti-Entamoeba histolytica scaffolds 28 with low micromolar activity including MMV675968 (IC 50 = 2.10 µM), MMV688179 (IC 50 = 2.38 29 µM) and MMV688844 (IC 50 = 5.63 µM). Structure-Activity-Relationship (SAR) studies led to 30 identification of two analogs ~100 fold more potent and selective than the original hit compound 31 1 (MMV675968): 1k (IC 50 = 0.043 µM) and 1l (IC 50 = 0.055 µM). Predictive analysis using 32 Maestro 11.6 suggested that these hit compounds possess acceptable physicochemical and 33 metabolism properties. These lead compounds are therefore good starting points for lead 34 optimization studies towards identification of drug candidate against amoebiasis. 35 36 37 38 39 40 3 41 Author Summary 42Diarrhoea is a leading cause of death for millions of children worldwide. One of the top 15 causes 43 of severe diarrhoea is Entamoeba histolytica, causing amoebiasis. What makes E. histolytica 44 dangerous is its ability to disseminate easily through a given population via contaminated food and 45 water supplies. Moreover, E. histolytica is quite comfortable in the environment, difficult to kill 46 with chorine and infect people at a very low dose, making it a priority pathogen to eradicate. Many 47 drugs have been developed so far to cure this infection. However, they are not efficient enough to 48 control the disease due to pathogen resistance that is becoming a big issue. In addition to that, 49 almost all the drugs in use are highly toxic to human causing several side effects upon medications. 50 Therefore, new, more efficient and less toxic drugs are urgently needed for the better management 51 of amoebiasis. Since the development of a new drug takes years, repurposing existing drugs has 52 been shown to shortcut the process and boost the discovery rate of new medicines. Using this same 53 approach, we have identified two compounds that potently inhibit E. histolytica and are nontoxic 54 that can enter the drug discovery pipeline for new amoebicidal drug development. Moreover, these 55 new inhibitors could also serve as starting points for the synthesis of a library of amoebicidal 56 compounds. 57 58 59 60 61 4 62 Introduction 63 Diarrhoea that is credited to have caused approximately 8% of all deaths among children under 64 age 5 worldwide in 2016 is considered as a leading executioner of children. Basically, the number 65 of yearly deaths among children is about ...

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“…The persister frequency assay was performed as described in Ross et al (38). An overnight culture of B. cenocepacia K56-2 was subcultured to a concentration of 1×10 8 CFU/mL in 2 mL LB.…”

Section: Methodsmentioning

confidence: 99%

New auranofin analogs with antibacterial properties against Burkholderia clinical isolates

Maydaniuk

Truong

et al. 2021

Preprint

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Bacteria of the genus Burkholderia includes pathogenic Burkholderia mallei, Burkholderia pseudomallei and the Burkholderia cepacia complex (Bcc). These Gram-negative pathogens have intrinsic drug resistance, which makes treatment of infections difficult. Bcc affects individuals with cystic fibrosis (CF) and the species B. cenocepacia is associated with one of the worst clinical outcomes. Following the repurposing of auranofin as an antibacterial against Gram-positive bacteria, we previously synthetized auranofin analogs with activity against Gram-negatives. In this work, we show two auranofin analogs, MS-40 and MS-40S have antibiotic activity against Burkholderia clinical isolates. The compounds are bactericidal against B. cenocepacia and kill stationary-phase cells and persisters without selecting for spontaneous resistance. Caenorhabditis elegans and Galleria mellonella tolerated high concentrations of MS-40 and MS-40S, demonstrating these compounds are not toxic in these models organisms. In summary, we show that MS-40 and MS-40S have the potential to be effective therapeutic options to treat Burkholderia infections.

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Evaluating New Compounds to Treat Burkholderia pseudomallei Infections

Cited by 30 publications

References 34 publications

Drug screening to identify compounds to act as co-therapies for the treatment of Burkholderia species

Drug screening to identify compounds to act as co-therapies for the treatment of Burkholderia species

Screening the MMV Open Access Pathogen box unveils novel and potent inhibitors of Amoebiasis agent: Entamoeba histolytica

New auranofin analogs with antibacterial properties against Burkholderia clinical isolates

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