Article
Pharmacology & Pharmacy
Diksha Kumari, Summaya Perveen, Rashmi Sharma, Kuljit Singh
Summary: Leishmaniasis is considered a neglected tropical disease by WHO and ranks second to malaria in terms of lethality. Accurate diagnosis is crucial due to involvement of multiple Leishmania species. New treatment methods for leishmaniasis include host-directed therapies, drug repurposing, nanotechnology, and combinational therapy.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Review
Biotechnology & Applied Microbiology
Prakash Kumar, Pawan Kumar, Nidhi Singh, Salil Khajuria, Rahul Patel, Vinod Kumar Rajana, Debabrata Mandal, Ravichandiran Velayutham
Summary: Visceral leishmaniasis is a deadly disease that affects hundreds of thousands of people each year. Current treatment options have limitations, such as drug resistance and toxicity, and are expensive. The development of nanofomulation-based AmB for improved delivery and various AmB nanoformulations have shown promise in overcoming these limitations.
FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY
(2022)
Article
Immunology
Sakib Burza, Raman Mahajan, Shahwar Kazmi, Neal Alexander, Deepak Kumar, Vikash Kumar, Estrella Lasry, Amit Harshana, Alan de Lima Pereira, Pradeep Das, Neena Verma, Vidya Nand Ravi Das, Chandra Shekhar Lal, Bharat Rewari, Vishal Goyal, Suman Rijal, Fabiana Alves, Naresh Gill, Krishna Pandey
Summary: This study conducted in a hospital in India compared two different treatment regimens for 150 patients with HIV and VL. The results showed that combination therapy is safe, well-tolerated, effective, and reduces treatment duration.
CLINICAL INFECTIOUS DISEASES
(2022)
Review
Engineering, Biomedical
Yu Zhang, Pan He, Peng Zhang, Xuan Yi, Chunsheng Xiao, Xuesi Chen
Summary: Polypeptides are important biodegradable polymers widely used in drug delivery for cancer treatment. Conjugating anticancer drugs with polypeptides offers advantages in improving pharmacokinetics, enhancing targeting, and controlling drug release, contributing to enhanced therapeutic outcomes with reduced side effects.
ADVANCED HEALTHCARE MATERIALS
(2021)
Article
Biochemistry & Molecular Biology
Aakriti Singh, Ganesh Yadagiri, Manorma Negi, Anurag Kumar Kushwaha, Om Prakash Singh, Shyam Sundar, Shyam Lal Mudavath
Summary: In this study, carboxymethyl chitosan (CMC) grafted lipid nanoformulations were prepared as an efficient carrier for amphotericin B (AmB) to treat leishmaniasis. The nanoformulations showed good physicochemical characteristics, controlled drug release, and high antileishmanial activity without causing toxicity.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2022)
Article
Biochemistry & Molecular Biology
Camila S. Freitas, Daniela P. Lage, Amanda S. Machado, Danniele L. Vale, Vivian T. Martins, Jamille M. O. Cardoso, Joao A. Oliveira-da-Silva, Thiago A. R. Reis, Grasiele S. V. Tavares, Fernanda F. Ramos, Fernanda Ludolf, Isabela A. G. Pereira, Raquel S. Bandeira, Ricardo T. Fujiwara, Lilian L. Bueno, Bruno M. Roatt, Miguel A. Chavez-Fumagalli, Eduardo A. F. Coelho
Summary: In this study, ivermectin (IVE) was found to be effective in reducing infection and parasite load in Leishmania donovani- and L. amazonensis-infected macrophages. It also increased the production of IFN-gamma and IL-12, while decreasing levels of IL-4 and IL-10.
Article
Infectious Diseases
Marta H. Branquinha, Pedro S. S. Araujo, Simone S. C. Oliveira, Leandro S. Sangenito, Diego S. Goncalves, Sergio H. Seabra, Claudia M. d'Avila-Levy, Andre L. S. Santos
Summary: The combination of MDL28170 and amphotericin B may provide a new alternative for the treatment of leishmaniasis, causing severe morphophysiological changes in parasite cells and affecting the Leishmania-macrophage interaction.
TROPICAL MEDICINE AND INFECTIOUS DISEASE
(2022)
Article
Multidisciplinary Sciences
Sina Bahraminejad, Abbas Pardakhty, Iraj Sharifi, Alireza Keyhani, Ehsan Salarkia, Mehdi Ranjbar
Summary: Leishmaniasis is a widespread neglected vector-borne protozoan disease that poses a major public health concern, with 12 million people affected worldwide and 60,000 deaths annually. Current chemotherapies for leishmaniasis have several drawbacks and side effects, prompting the development of new drug delivery systems. Layered double hydroxides (LDHs) have recently been considered due to their unique characteristics.
Article
Pharmacology & Pharmacy
Guilherme S. Ramos, Virginia M. R. Vallejos, Gabriel S. M. Borges, Raquel M. Almeida, Izabela M. Alves, Marta M. G. Aguiar, Christian Fernandes, Pedro P. G. Guimaraes, Ricardo T. Fujiwara, Philippe M. Loiseau, Lucas A. M. Ferreira, Frederic Frezard
Summary: This study developed a formulation of PEGylated liposomal AmB and compared its efficacy to AmBisome (R) in a murine model of cutaneous leishmaniasis (CL). The results showed that the PEGylated formulation significantly reduced lesion growth and parasite load in the treatment of CL, both through parenteral and oral routes.
Article
Microbiology
Maria Ubals, Pau Bosch-Nicolau, Adrian Sanchez-Montalva, Fernando Salvador, Gloria Aparicio-Espanol, Elena Sulleiro, Aroa Silgado, Antoni Soriano-Arandes, Maria Espiau, Berta Ferrer, Diana Pou, Begona Trevino, Israel Molina, Vicente Garcia-Patos
Summary: The study described a cohort of patients with complex cutaneous leishmaniasis (CL), with a focus on the treatment outcome of liposomal amphotericin B (L-AmB). Results showed that all patients were considered cured within the first year post-treatment, and there were no treatment failures with L-AmB for complex CL.
Article
Parasitology
Maria Jose Alves de Oliveira, Gethzemani Mayeli Estrada Villegas, Flavia Daniela Motta, Omar Fabela-Sanchez, Arian Espinosa-Roa, Wesley Luzetti Fotoran, Janaina Capelli Peixoto, Fabia Tomie Tano, Ademar Benevolo Lugao, Pablo Antonio Salvador Vasquez
Summary: The study focused on analyzing the effects of Cobalt-60 gamma irradiation on crosslinking polymeric hydrogels containing Amphotericin B, in order to develop an alternative treatment method for leishmaniasis. The irradiated Hydg/Amph-B showed similar stability to the standard Amph-B solution and effectively inhibited L. amazonensis promastigotes, demonstrating its potential as a promising alternative therapy.
Article
Multidisciplinary Sciences
Surendra Rajit Prasad, Prakash Kumar, Saptarshi Mandal, Anu Mohan, Radhika Chaurasia, Ashish Shrivastava, Pallaprolu Nikhil, Dande Aishwarya, P. Ramalingam, Rahul Gajbhiye, Shriya Singh, Arunava Dasgupta, Mukesh Chourasia, V. Ravichandiran, Prolay Das, Debabrata Mandal
Summary: In this study, we evaluated the effectiveness of different types of saturated medium-chain fatty acids against Leishmania. We found that caprylic acid (CA) showed the most potent anti-leishmanial effect. Further investigation revealed that CA mediates cell death by depleting ergosterol through inhibiting the enzyme mevalonate kinase (MevK) in the ergosterol biosynthesis pathway. This study provides insights into the mechanism of CA against visceral leishmaniasis.
SCIENTIFIC REPORTS
(2022)
Article
Instruments & Instrumentation
Manuela Carvalheiro, Jennifer Vieira, Catarina Faria-Silva, Joana Marto, Sandra Simoes
Summary: Cutaneous leishmaniasis (CL) is a chronic skin disease characterized by skin lesions that may cause permanent scars. This study optimized a deformable lipid vesicle (DLV) for the topical administration of Amphotericin B (AmB) and found it to be effective in reducing parasite viability in skin layers. DLV may represent a cost-effective and safe therapeutic option in CL treatment.
DRUG DELIVERY AND TRANSLATIONAL RESEARCH
(2021)
Article
Microbiology
Chonlada Mano, Aphisek Kongkaew, Pongsri Tippawangkosol, Pradya Somboon, Sittiruk Roytrakul, Pascale Pescher, Gerald F. Spaeth, Chairat Uthaipibull, Adisak Tantiworawit, Padet Siriyasatien, Narissara Jariyapan
Summary: Amphotericin B (AmpB) deoxycholate is the first-line drug for visceral leishmaniasis caused by Leishmania martiniquensis, but cases of AmpB treatment failure have been reported in Thailand. This study investigated the fitness changes of AmpB-resistant strains and found that they exhibited increased metacyclogenesis, growth, and infectivity compared to susceptible strains. The AmpB-resistant strains were present in mice for longer periods and could be efficiently transmitted to humans, potentially facilitated by asymptomatic hosts. Monitoring for AmpB-resistant L. martiniquensis is therefore crucial, especially in relapsing leishmaniasis and asymptomatic patients, particularly those coinfected with HIV/Leishmania.
FRONTIERS IN MICROBIOLOGY
(2023)
Article
Instruments & Instrumentation
Lipika Ray, R. Karthik, Vikas Shrivastava, Sheelendra Pratap Singh, A. B. Pant, Neena Goyal, Kailash C. Gupta
Summary: A nanoformulation of AmB and Pip was developed, with controlled release properties and protection from acidic pH, showing enhanced drug bioavailability, non-nephrotoxic nature, and potential antileishmanial activity up to 96% inhibition of the parasite in vivo in the golden hamster-L. donovani model.
DRUG DELIVERY AND TRANSLATIONAL RESEARCH
(2021)
Article
Chemistry, Medicinal
Barbara Forte, Sabine Ottilie, Andrew Plater, Brice Campo, Koen J. Dechering, Francisco Javier Gamo, Daniel E. Goldberg, Eva S. Istvan, Marcus Lee, Amanda K. Lukens, Case W. McNamara, Jacquin C. Niles, John Okombo, Charisse Flerida A. Pasaje, Miles G. Siegel, Dyann Wirth, Susan Wyllie, David A. Fidock, Beatriz Baragana, Elizabeth A. Winzeler, Ian H. Gilbert
Summary: This paper discusses the important criteria for selecting drug targets in antimalarial drug discovery, as well as the analysis of several drug targets in the MaIDA pipeline. Prioritizing targets ready to enter the drug discovery process can increase the likelihood of progressible drug candidates.
ACS INFECTIOUS DISEASES
(2021)
Article
Microbiology
Marta L. Lima, Lindsay B. Tulloch, Victoriano Corpas-Lopez, Sandra Carvalho, Richard J. Wall, Rachel Milne, Eva Rico, Stephen Patterson, Ian H. Gilbert, Sonia Moniz, Lorna MacLean, Leah S. Torrie, Carmine Morgillo, David Horn, Fabio Zuccotto, Susan Wyllie
Summary: Phenotypic screening has identified a potential compound for treating Chagas' disease caused by Trypanosoma cruzi. Further studies have revealed the compound's primary target and identified potential secondary targets. These findings provide new insights for the discovery of anti-Chagas drugs.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Obstetrics & Gynecology
Franz S. Gruber, Zoe C. Johnston, Neil R. Norcross, Irene Georgiou, Caroline Wilson, Kevin D. Read, Ian H. Gilbert, Jason R. Swedlow, Sarah Martins da Silva, Christopher L. R. Barratt
Summary: This study utilized a high-throughput screening platform to identify compounds that can enhance sperm motility, providing a promising starting point for male fertility drug discovery.
HUMAN REPRODUCTION
(2022)
Review
Developmental Biology
Zoe C. Johnston, Franz S. Gruber, Sean G. Brown, Neil R. Norcross, Jason Swedlow, Ian H. Gilbert, Christopher L. R. Barratt
Summary: Despite recent advances, there is still incomplete understanding of male infertility and male non-hormonal contraceptives. Direct observation of compounds' effects on sperm function can increase knowledge and advance the field.
Article
Microbiology
Fabio Tamaki, Fabio Fisher, Rachel Milne, Fernando Sanchez-Roman Teran, Natalie Wiedemar, Karolina Wrobel, Darren Edwards, Hella Baumann, Ian H. Gilbert, Beatriz Baragana, Jake Baum, Susan Wyllie
Summary: Artemisinin-based combination therapies have played a crucial role in reducing the global burden of malaria. However, the emergence of resistance in Southeast Asia and sub-Saharan Africa is now threatening their efficacy. Therefore, there is an urgent need to develop new antimalarials with diverse mechanisms of action.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Chemistry, Medicinal
Alasdair Smith, Richard J. Wall, Stephen Patterson, Tim Rowan, Eva Rico Vidal, Laste Stojanovski, Margaret Huggett, Shahienaz E. Hampton, Michael G. Thomas, Victoriano Corpas Lopez, Kirsten Gillingwater, Jeff Duke, Grant Napier, Rose Peter, Herve S. Vitouley, Justin R. Harrison, Rachel Milne, Laura Jeacock, Nicola Baker, Susan H. Davis, Frederick Simeons, Jennifer Riley, David Horn, Reto Brun, Fabio Zuccotto, Michael J. Witty, Susan Wyllie, Kevin D. Read, Ian H. Gilbert
Summary: African animal trypanosomiasis is a major problem in cattle and other livestocks in sub-Saharan Africa and current treatments are facing drug resistance. A medicinal chemistry program has developed a lead compound capable of curing cattle infected with two types of trypanosomes via intravenous dosing, with potential for further optimization to provide a single-dose intramuscular treatment for this disease.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Kate McGonagle, Gary J. Tarver, Juan Cantizani, Ignacio Cotillo, Peter G. Dodd, Liam Ferguson, Ian H. Gilbert, Maria Marco, Tim Miles, Claire Naylor, Maria Osuna-Cabello, Christy Paterson, Kevin D. Read, Erika G. Pinto, Jennifer Riley, Paul Scullion, Yoko Shishikura, Frederick Simeons, Laste Stojanovski, Nina Svensen, John Thomas, Paul G. Wyatt, Pilar Manzano, Manu De Rycker, Michael G. Thomas
Summary: This study describes a series of disubstituted piperazines with good potency against Trypanosoma cruzi, but poor metabolic stability. Strategies such as lowering logD, bioisosteric replacements, and plate-based arrays are used to address this issue. The challenges of improving pharmacokinetic profile while maintaining potency are discussed.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Correction
Microbiology
Manu De Rycker, Susan Wyllie, David Horn, Kevin D. Read, Ian H. Gilbert
NATURE REVIEWS MICROBIOLOGY
(2022)
Review
Microbiology
Manu De Rycker, Susan Wyllie, David Horn, Kevin D. Read, Ian H. Gilbert
Summary: Leishmaniasis, Chagas disease, and human African trypanosomiasis are major causes of death and illness, particularly in low- and middle-income countries. The development of new medicines for leishmaniasis and Chagas disease is urgently needed, with limited progress in the clinical pipeline for Chagas disease. This review provides an overview of recent advances in understanding the biology of these pathogens, with a focus on drug discovery, as well as the development of new drug candidates and potential solutions to overcome challenges in clinical development.
NATURE REVIEWS MICROBIOLOGY
(2023)
Article
Multidisciplinary Sciences
Simon R. Green, Susan H. Davis, Sebastian Damerow, Curtis A. Engelhart, Michael Mathieson, Beatriz Baragana, David A. Robinson, Jevgenia Tamjar, Alice Dawson, Fabio K. Tamaki, Kirsteen Buchanan, John Post, Karen Dowers, Sharon M. Shepherd, Chimed Jansen, Fabio Zuccotto, Ian H. Gilbert, Ola Epemolu, Jennifer Riley, Laste Stojanovski, Maria Osuna-Cabello, Esther Perez-Herran, Maria Jose Rebollo, Laura Guijarro Lopez, Patricia Casado Castro, Isabel Camino, Heather C. Kim, James M. Bean, Navid Nahiyaan, Kyu Y. Rhee, Qinglan Wang, Vee Y. Tan, Helena I. M. Boshoff, Paul J. Converse, Si-Yang Li, Yong S. Chang, Nader Fotouhi, Anna M. Upton, Eric L. Nuermberger, Dirk Schnappinger, Kevin D. Read, Lourdes Encinas, Robert H. Bates, Paul G. Wyatt, Laura A. T. Cleghorn
Summary: Tuberculosis is a major cause of mortality globally, and the emergence of drug-resistant strains of Mycobacterium tuberculosis necessitates the urgent development of safe and effective treatments. In this study, a compound against lysyl-tRNA synthetase is developed, demonstrating targeted mechanism of action and in vivo efficacy.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Medicinal
Rachel Milne, Natalie Wiedemar, Victoriano Corpas-Lopez, Eoin Moynihan, Richard J. Wall, Alice Dawson, David A. Robinson, Sharon M. Shepherd, Robert J. Smith, Irene Hallyburton, John M. Post, Karen Dowers, Leah S. Torrie, Ian H. Gilbert, Beatriz Baragana, Stephen Patterson, Susan Wyllie
Summary: There is a need for new medicines to prevent and treat malaria. This study describes the development of a toolkit to support the therapeutic exploitation of a promising target, lysyl tRNA synthetase (PfKRS), using target-focused approaches.
ACS INFECTIOUS DISEASES
(2022)
Review
Chemistry, Medicinal
Neil R. Norcross, Irene Georgiou, Zoe C. Johnston, Franz S. Gruber, Jason R. Swedlow, Kevin D. Read, Christopher LR. Barratt, Ian H. Gilbert
Summary: This article discusses the need for male contraceptives and explores the characteristics and potential development pathways of male contraceptives. It also examines various approaches to discovering male contraceptives and highlights potential targets discussed in the literature.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Microbiology
Manu De Rycker, Susan Wyllie, David Horn, Kevin D. Read, Ian H. Gilbert
Summary: Leishmaniasis, Chagas disease, and human African trypanosomiasis are causing significant death and morbidity, especially in low- and middle-income countries. There is a critical need for new medications for leishmaniasis and Chagas disease, while the clinical development pipeline for Chagas disease remains sparse. This review discusses recent advancements in understanding the biology of these pathogens, with a focus on drug discovery, and explores progress in developing new drug candidates and identifying potential molecular targets. The challenges in developing new clinical candidates are also discussed, along with potential solutions to overcome these hurdles.
NATURE REVIEWS MICROBIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Robert L. Summers, Charisse Flerida A. Pasaje, Joao P. Pisco, Josefine Striepen, Madeline R. Luth, Krittikorn Kumpornsin, Emma F. Carpenter, Justin T. Munro, De Lin, Andrew Plater, Avinash S. Punekar, Andrew M. Shepherd, Sharon M. Shepherd, Manu Vanaerschot, James M. Murithi, Kelly Rubiano, Asli Akidi, Sabine Ottilie, Nimisha Mittal, A. Hazel Dilmore, Madalyn Won, Rebecca E. K. Mandt, Kerry McGowen, Edward Owen, Chris Walpole, Manuel Llinas, Marcus C. S. Lee, Elizabeth A. Winzeler, David A. Fidock, Ian H. Gilbert, Dyann F. Wirth, Jacquin C. Niles, Beatriz Baragana, Amanda K. Lukens
Summary: In this study, we identified and validated the Plasmodium falciparum acetyl-coenzyme A synthetase (PfAcAS) as an important, druggable target. Genetic and chemical validation confirmed that mutations in PfAcAS confer resistance to two antiplasmodial compounds and that these compounds directly inhibit the enzyme. We also found that PfAcAS is essential for asexual growth and involved in the epigenetic regulation of gene expression.
CELL CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Luciana S. Paradela, Richard J. Wall, Sandra Carvalho, Giulia Chemi, Victoriano Corpas-Lopez, Eoin Moynihan, Davide Bello, Stephen Patterson, Maria Lucia S. Guther, Alan H. Fairlamb, Michael A. J. Ferguson, Fabio Zuccotto, Julio Martin, Ian H. Gilbert, Susan Wyllie
Summary: A benzothiophene compound with activity against Leishmania donovani was found, with oxidosqualene cyclase (OSC) identified as its target. The amplification of the OSC gene was associated with resistance to the compound, and introduction of an ectopic copy of the gene reduced susceptibility. Biochemical analyses showed substrate accumulation and product depletion in cells treated with the compound, confirming direct binding of the compound to OSC.
CELL CHEMICAL BIOLOGY
(2021)
