Publications by authors named "Bart Staker"

Plasmodium vivax, a significant contributor to global malaria cases, poses an escalating health burden on a substantial portion of the world's population. The increasing spread of P. vivax because of climate change underscores the development of new and rational drug-discovery approaches.

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Griselimycin, a cyclic depsidecapeptide produced by Streptomyces griseus, is a promising lead inhibitor of the sliding clamp component of bacterial DNA polymerases (β-subunit of Escherichia coli DNA pol III). It was previously shown to inhibit the Mycobacterium tuberculosis β-clamp with remarkably high affinity and selectivity - the peptide lacks any interaction with the human sliding clamp. Here, we used a structural genomics approach to address the prospect of broader-spectrum inhibition, in particular of β-clamps from Gram-negative bacterial targets.

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Nontuberculous mycobacteria (NTM) are emerging human pathogens linked to severe pulmonary diseases. Current treatments involve the prolonged use of multiple drugs and are often ineffective. Bacterial dihydrofolate reductase (DHFR) is a key enzyme targeted by antibiotics in Gram-negative bacterial infections.

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  • Leishmania is a protozoan parasite that causes serious diseases such as cutaneous and visceral leishmaniasis, heavily impacting impoverished communities with limited medical resources.
  • Current treatments are toxic and not very effective, prompting the need for research into the parasite's metabolism to find new drug targets.
  • The study focused on the unique enzyme LiAcs1 from Leishmania infantum, which has both acetyl-CoA synthetase and acetoacetyl-CoA synthetase activities, revealing it as a promising target for developing selective inhibitors to disrupt the parasite's critical metabolic pathways.
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  • Plasmodium vivax causes malaria, affecting about a third of the world's population, and primaquine treatment is unsafe for those with G6PD deficiency, which impacts a significant portion of people in endemic areas.
  • The Seattle Structural Genomics Center for Infectious Disease studied PvNMT (N-myristoyltransferase) to find alternative drug targets since it's essential for P. vivax survival by facilitating protein modification.
  • The newly solved crystal structure of PvNMT, showing its interaction with myristoyl-CoA and a novel inhibitor, reveals differences from human enzymes, providing insights for creating effective antimalarial drugs.
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  • * Recent studies indicate that human enolase 2 (ENO2) inhibitors, particularly a compound called HEX, show significant potential in targeting N. fowleri by blocking its glucose metabolism, making it toxic to these pathogens.
  • * While HEX treatment extended the survival of infected rodents significantly compared to untreated controls, it did not fully eradicate the amoebae in their brains, indicating a need for further research to optimize its use as a treatment for primary amoebic meningoencephalitis (PAM).
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-myristoyltransferase (NMT) is a promising antimalarial drug target. Despite biochemical similarities between and human NMTs, our recent research demonstrated that high selectivity is achievable. Herein, we report NMT-inhibiting compounds aimed at identifying novel mechanisms of selectivity.

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The rise in antimicrobial resistance is a global health crisis and necessitates the development of novel strategies to treat infections. For example, in 2022 tuberculosis (TB) was the second leading infectious killer after COVID-19, with multi-drug-resistant strains of TB having an ∼40% fatality rate. Targeting essential biosynthetic pathways in pathogens has proven to be successful for the development of novel antimicrobial treatments.

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The transmembrane serine protease 2 (TMPRSS2) activates the outer structural proteins of a number of respiratory viruses including influenza A virus (IAV), parainfluenza viruses, and various coronaviruses for membrane fusion. Previous studies showed that TMPRSS2 interacts with the carboxypeptidase angiotensin-converting enzyme 2 (ACE2), a cell surface protein that serves as an entry receptor for some coronaviruses. Here, by using protease activity assays, we determine that ACE2 increases the enzymatic activity of TMPRSS2 in a non-catalytic manner.

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Malaria remains a significant public health challenge, with being the species responsible for the most prevalent form of the disease. Given the limited therapeutic options available, the search for new antimalarials against is urgent. This study aims to identify new inhibitors for -myristoyltransferase (PvNMT), an essential drug target against malaria.

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Controlling malaria requires new drugs against . The cGMP-dependent protein kinase (PfPKG) is a validated target whose inhibitors could block multiple steps of the parasite's life cycle. We defined the structure-activity relationship (SAR) of a pyrrole series for PfPKG inhibition.

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Infections with the pathogenic free-living amoebae can lead to life-threatening illnesses including catastrophic primary amebic meningoencephalitis (PAM). Efficacious treatment options for these infections are lacking and the mortality rate remains >95% in the US. Glycolysis is very important for the infectious trophozoite lifecycle stage and inhibitors of glucose metabolism have been found to be toxic to the pathogen.

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  • * Inorganic pyrophosphatases (PPases) break down PP into orthophosphates, preventing toxic buildup and providing usable phosphate for biosynthesis.
  • * The study reports a crystal structure of L. pneumophila's family I PPase at high resolution, revealing its hexameric structure and preference for Mg as a cofactor, which is significant due to the bacterium's link to Legionnaires' disease.
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  • Around 50,000 children under 5 die annually from diarrhea caused by a protozoan parasite, with no effective drugs or vaccines currently available.
  • Researchers conducted a high throughput screening (HTS) of compounds to find potential drugs targeting a protein called N-myristoyltransferase (NMT), which is a validated target in similar parasites.
  • Two promising compounds were identified and tested against NMT, revealing different binding site conformations that offer insight for designing new selective inhibitors.
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Drugs targeting multiple stages of the Plasmodium vivax life cycle are needed to reduce the health and economic burdens caused by malaria worldwide. N-myristoyltransferase (NMT) is an essential eukaryotic enzyme and a validated drug target for combating malaria. However, previous PvNMT inhibitors have failed due to their low selectivity over human NMTs.

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SARS-CoV-2 is the agent responsible for acute respiratory disease COVID-19 and the global pandemic initiated in early 2020. While the record-breaking development of vaccines has assisted the control of COVID-19, there is still a pressing global demand for antiviral drugs to halt the destructive impact of this disease. Repurposing clinically approved drugs provides an opportunity to expediate SARS-CoV-2 treatments into the clinic.

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  • Fungal infections are a major health threat, causing approximately 150 million severe cases and 1.7 million deaths yearly, highlighting the need for new antifungal drugs due to the rise of multidrug-resistant strains.
  • The PanK enzyme in fungi is crucial for utilizing pantothenic acid and is the first step in coenzyme A biosynthesis, with a single PanK gene present in sequenced fungi.
  • Researchers have determined the crystal structure of fungal PanK, identifying new inhibitors that could effectively target and inhibit the growth of Candida species, positioning PanK as a promising target for new antifungal treatments.
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E-cadherin adhesion is regulated at the cell surface, a process that can be replicated by activating antibodies. We use cryo-electron microscopy (EM) and X-ray crystallography to examine functional states of the cadherin adhesive dimer. This dimer is mediated by N-terminal beta strand-swapping involving Trp2, and forms via a different transient X-dimer intermediate.

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E-cadherin (Ecad) is an essential cell-cell adhesion protein with tumor suppression properties. The adhesive state of Ecad can be modified by the monoclonal antibody 19A11, which has potential applications in reducing cancer metastasis. Using X-ray crystallography, we determine the structure of 19A11 Fab bound to Ecad and show that the antibody binds to the first extracellular domain of Ecad near its primary adhesive motif: the strand-swap dimer interface.

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The name of one of the authors in Beard et al. [(2022), Acta Cryst. F78, 59-65] is corrected.

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Chlamydia trachomatis is the leading cause of bacterial sexually transmitted infections globally and is one of the most commonly reported infections in the United States. There is a need to develop new therapeutics due to drug resistance and the failure of current treatments to clear persistent infections. Structures of potential C.

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Giardiasis is the most prevalent diarrheal disease globally and affects humans and animals. It is a significant problem in developing countries, the number one cause of travelers' diarrhea and affects children and immunocompromised individuals, especially HIV-infected individuals. Giardiasis is treated with antibiotics (tinidazole and metronidazole) that are also used for other infections such as trichomoniasis.

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Members of the bacterial genus Brucella cause brucellosis, a zoonotic disease that affects both livestock and wildlife. Brucella are category B infectious agents that can be aerosolized for biological warfare. As part of the structural genomics studies at the Seattle Structural Genomics Center for Infectious Disease (SSGCID), FolM alternative dihydrofolate reductases 1 from Brucella suis and Brucella canis were produced and their structures are reported.

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Paraburkholderia xenovorans degrades organic wastes, including polychlorinated biphenyls. The atomic structure of a putative dehydrogenase/reductase (SDR) from P. xenovorans (PxSDR) was determined in space group P2 at a resolution of 1.

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