Aya Hefnawy - Academia.edu (original) (raw)

Papers by Aya Hefnawy

Trends in Parasitology, 2017

New drugs are needed to control leishmaniasis and efforts are currently ongoing to counter the ne... more New drugs are needed to control leishmaniasis and efforts are currently ongoing to counter the neglect of this disease. We discuss here the utility and the impact of associating drug resistance (DR) studies to drug discovery pipelines. We use as paradigm currently used drugs, antimonials and miltefosine, and complement our reflection by interviewing three experts in the field. We suggest DR studies to be involved at two different stages of drug development: (i) the efficiency of novel compounds should be confirmed on sets of strains including recent clinical isolates with DR; (ii) experimental DR should be generated to promising compounds at an early stage of their development, to further optimize them and monitor clinical trials. Current Options and Challenges for Visceral Leishmaniasis Treatment: Could We Benefit from Drug Resistance Studies? The genus Leishmania (Trypanosomatidae) comprises several species of digenetic parasites transmitted as flagellated promastigotes by sand fly vectors and infecting reticuloendothelial cells of mammal hosts as intracellular amastigotes. The parasites are equipped with massive host subversion machinery [1,2] and cause a spectrum of clinical forms, ranging from benign cutaneous lesions to a fatal visceral syndrome, [ 5 6 _ T D $ D I F F ] kala-[ 5 7 _ T D $ D I F F ] azar (or visceral leishmaniasis, VL). The complex of leishmaniases is endemic in tropical and subtropical countries, including Europe [3], associated with poverty and classified among the most neglected tropical diseases (NTDs) [4]: for long, it only received limited attention from authorities, funding bodies[ 3 _ T D $ D I F F ] and private companies.

Scientific Reports, 2018

The growing drug resistance (DR) raises major concerns for the control of visceral leishmaniasis ... more The growing drug resistance (DR) raises major concerns for the control of visceral leishmaniasis (VL), a neglected disease lethal in 95 percent of the cases if left untreated. Resistance has rendered antimonials (SSG) obsolete in the Indian Sub-Continent (ISC) and the first miltefosine-resistant Leishmania donovani were isolated. New chemotherapeutic options are needed and novel compounds are being identified by high-throughput screening (HTS). HTS is generally performed with old laboratory strains such as LdBOB and we aimed here to validate the activity of selected compounds against recent clinical isolates. In this academic/industrial collaboration, 130 compounds from the GSK "Leishbox" were screened against one SSG-sensitive and one SSG-resistant strain of L. donovani recently isolated from ISC patients, using an intracellular assay of L. donovani-infected THP1-derived macrophages. We showed that only 45% of the compounds were active in both clinical isolates and LdBOB. There were also different compound efficiencies linked to the SSG susceptibility background of the strains. In addition, our results suggested that the differential susceptibility profiles were chemical series-dependent. In conclusion, we demonstrate the potential value of including clinical isolates (as well as resistant strains) in the HTS progression cascade. Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania 1. It occurs in several parts of the world under different clinical forms, the most severe being visceral leishmaniasis (VL), also known as kala-azar; a systemic illness that is lethal if left untreated. Every year, 200,000-400,000 new cases of VL happen, due to parasites of the L. donovani complex, essentially in India, Nepal, Bangladesh, Sudan, Ethiopia and Brazil, with a mortality estimated at 10% 1. In the Indian sub-continent (ISC) a regional program aiming for the elimination of VL (Kala-Azar elimination program or KAEP) is currently running, based on two major pillars, vector control and chemotherapy 2. Currently, there are only few therapeutic options for leishmaniasis and they have various drawbacks 3. Pentavalent antimonials (SSG) were used for decades, but they are limited by toxicity and treatment failure (TF) primarily caused by resistant parasites. This led to the progressive withdrawal of SSG in the Indian Sub-Continent (ISC) since 2005 4. At that time, SSG was replaced by Miltefosine (MIL), the first oral treatment available for leishmaniasis 5. However the use of MIL is being threatened by the alarming rise of TF in the ISC 6 and recently, the first MIL-resistant strains were detected in the field 7. The development of a liposomal form of Amphotericin B (Ambisome) has reduced its toxicity but its availability to patients is restricted by high costs 8. Preferential pricing agreement increased access to Ambisome and a single-dose treatment is now used as the first line treatment in the ISC 9. Combination therapies are used as an alternative, but this strategy might be questioned, when one of the composing drug is starting to fail (like MIL); in addition, experimental work has shown that L. donovani resistant to combined drugs could easily be selected in vitro 10. Currently there are no other drugs available, and new compounds, formulations or combinations are urgently needed. High-throughput screening (HTS) is an efficient way of identifying active compounds 11,12 able to eliminate the parasite without affecting the host. Whole-cell phenotypic HTS is used for anti-leishmania drug discovery because of the low number of molecular targets well characterized and validated 13. The parasite life stage used

mBio

Humans and their pathogens are continuously locked in a molecular arms race during which the even... more Humans and their pathogens are continuously locked in a molecular arms race during which the eventual emergence of pathogen drug resistance (DR) seems inevitable. For neglected tropical diseases (NTDs), DR is generally studied retrospectively once it has already been established in clinical settings.

The implementation of prospective drug resistance (DR) studies in the R&D pipelines is a common p... more The implementation of prospective drug resistance (DR) studies in the R&D pipelines is a common practice for many infectious diseases, but not for Neglected Tropical Diseases. Here, we explored and demonstrated the importance of this approach, using as paradigms Leishmania donovani, the etiological agent of Visceral Leishmaniasis (VL), and TCMDC-143345, a promising compound of the GSK ‘Leishbox’ to treat VL. We experimentally selected resistance to TCMDC-143345 in vitro and characterized resistant parasites at genomic and phenotypic levels. We found that it took more time to develop resistance to TCMDC-143345 than to other drugs in clinical use and that there was no cross resistance to these drugs, suggesting a new and unique mechanism. By whole genome sequencing, we found two mutations in the gene encoding the L. donovani dynamin-1-like protein (LdoDLP1) that were fixed at highest drug pressure. Through phylogenetic analysis, we identified LdoDLP1 as a family member of the dynamin-...

Trends in Parasitology, 2017

New drugs are needed to control leishmaniasis and efforts are currently ongoing to counter the ne... more New drugs are needed to control leishmaniasis and efforts are currently ongoing to counter the neglect of this disease. We discuss here the utility and the impact of associating drug resistance (DR) studies to drug discovery pipelines. We use as paradigm currently used drugs, antimonials and miltefosine, and complement our reflection by interviewing three experts in the field. We suggest DR studies to be involved at two different stages of drug development: (i) the efficiency of novel compounds should be confirmed on sets of strains including recent clinical isolates with DR; (ii) experimental DR should be generated to promising compounds at an early stage of their development, to further optimize them and monitor clinical trials. Current Options and Challenges for Visceral Leishmaniasis Treatment: Could We Benefit from Drug Resistance Studies? The genus Leishmania (Trypanosomatidae) comprises several species of digenetic parasites transmitted as flagellated promastigotes by sand fly vectors and infecting reticuloendothelial cells of mammal hosts as intracellular amastigotes. The parasites are equipped with massive host subversion machinery [1,2] and cause a spectrum of clinical forms, ranging from benign cutaneous lesions to a fatal visceral syndrome, [ 5 6 _ T D $ D I F F ] kala-[ 5 7 _ T D $ D I F F ] azar (or visceral leishmaniasis, VL). The complex of leishmaniases is endemic in tropical and subtropical countries, including Europe [3], associated with poverty and classified among the most neglected tropical diseases (NTDs) [4]: for long, it only received limited attention from authorities, funding bodies[ 3 _ T D $ D I F F ] and private companies.

Scientific Reports, 2018

The growing drug resistance (DR) raises major concerns for the control of visceral leishmaniasis ... more The growing drug resistance (DR) raises major concerns for the control of visceral leishmaniasis (VL), a neglected disease lethal in 95 percent of the cases if left untreated. Resistance has rendered antimonials (SSG) obsolete in the Indian Sub-Continent (ISC) and the first miltefosine-resistant Leishmania donovani were isolated. New chemotherapeutic options are needed and novel compounds are being identified by high-throughput screening (HTS). HTS is generally performed with old laboratory strains such as LdBOB and we aimed here to validate the activity of selected compounds against recent clinical isolates. In this academic/industrial collaboration, 130 compounds from the GSK "Leishbox" were screened against one SSG-sensitive and one SSG-resistant strain of L. donovani recently isolated from ISC patients, using an intracellular assay of L. donovani-infected THP1-derived macrophages. We showed that only 45% of the compounds were active in both clinical isolates and LdBOB. There were also different compound efficiencies linked to the SSG susceptibility background of the strains. In addition, our results suggested that the differential susceptibility profiles were chemical series-dependent. In conclusion, we demonstrate the potential value of including clinical isolates (as well as resistant strains) in the HTS progression cascade. Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania 1. It occurs in several parts of the world under different clinical forms, the most severe being visceral leishmaniasis (VL), also known as kala-azar; a systemic illness that is lethal if left untreated. Every year, 200,000-400,000 new cases of VL happen, due to parasites of the L. donovani complex, essentially in India, Nepal, Bangladesh, Sudan, Ethiopia and Brazil, with a mortality estimated at 10% 1. In the Indian sub-continent (ISC) a regional program aiming for the elimination of VL (Kala-Azar elimination program or KAEP) is currently running, based on two major pillars, vector control and chemotherapy 2. Currently, there are only few therapeutic options for leishmaniasis and they have various drawbacks 3. Pentavalent antimonials (SSG) were used for decades, but they are limited by toxicity and treatment failure (TF) primarily caused by resistant parasites. This led to the progressive withdrawal of SSG in the Indian Sub-Continent (ISC) since 2005 4. At that time, SSG was replaced by Miltefosine (MIL), the first oral treatment available for leishmaniasis 5. However the use of MIL is being threatened by the alarming rise of TF in the ISC 6 and recently, the first MIL-resistant strains were detected in the field 7. The development of a liposomal form of Amphotericin B (Ambisome) has reduced its toxicity but its availability to patients is restricted by high costs 8. Preferential pricing agreement increased access to Ambisome and a single-dose treatment is now used as the first line treatment in the ISC 9. Combination therapies are used as an alternative, but this strategy might be questioned, when one of the composing drug is starting to fail (like MIL); in addition, experimental work has shown that L. donovani resistant to combined drugs could easily be selected in vitro 10. Currently there are no other drugs available, and new compounds, formulations or combinations are urgently needed. High-throughput screening (HTS) is an efficient way of identifying active compounds 11,12 able to eliminate the parasite without affecting the host. Whole-cell phenotypic HTS is used for anti-leishmania drug discovery because of the low number of molecular targets well characterized and validated 13. The parasite life stage used

mBio

Humans and their pathogens are continuously locked in a molecular arms race during which the even... more Humans and their pathogens are continuously locked in a molecular arms race during which the eventual emergence of pathogen drug resistance (DR) seems inevitable. For neglected tropical diseases (NTDs), DR is generally studied retrospectively once it has already been established in clinical settings.

The implementation of prospective drug resistance (DR) studies in the R&D pipelines is a common p... more The implementation of prospective drug resistance (DR) studies in the R&D pipelines is a common practice for many infectious diseases, but not for Neglected Tropical Diseases. Here, we explored and demonstrated the importance of this approach, using as paradigms Leishmania donovani, the etiological agent of Visceral Leishmaniasis (VL), and TCMDC-143345, a promising compound of the GSK ‘Leishbox’ to treat VL. We experimentally selected resistance to TCMDC-143345 in vitro and characterized resistant parasites at genomic and phenotypic levels. We found that it took more time to develop resistance to TCMDC-143345 than to other drugs in clinical use and that there was no cross resistance to these drugs, suggesting a new and unique mechanism. By whole genome sequencing, we found two mutations in the gene encoding the L. donovani dynamin-1-like protein (LdoDLP1) that were fixed at highest drug pressure. Through phylogenetic analysis, we identified LdoDLP1 as a family member of the dynamin-...