drug discovery
Experimental TherapeuticsIn Vitro and In Vivo Characterization of Potent Antileishmanial Methionine Aminopeptidase 1 InhibitorsLeishmania major is the causative agent of cutaneous leishmaniasis (CL). No human vaccine is available for CL, and current drug regimens present several drawbacks, such as emerging resistance, severe toxicity, medium effectiveness, and/or high cost. Thus, the need for better treatment options against CL is a priority. In the present study, we validate the enzyme...
SusceptibilityIn Vitro Screening of the Open-Source Medicines for Malaria Venture Malaria and Pathogen Boxes To Discover Novel Compounds with Activity against Balamuthia mandrillarisBalamuthia mandrillaris is an under-reported, pathogenic free-living amoeba that causes Balamuthia amoebic encephalitis (BAE) and cutaneous skin infections. Although cutaneous infections are not typically lethal, BAE with or without cutaneous involvement is usually fatal. This is due to the lack of drugs that are both efficacious and can cross the blood-brain...
Chemistry; BiosynthesisA Biosynthetic Platform for Antimalarial Drug DiscoveryAdvances in synthetic biology have enabled the production of a variety of compounds using bacteria as a vehicle for complex compound biosynthesis. Violacein, a naturally occurring indole pigment with antibiotic properties, can be biosynthetically engineered in Escherichia coli expressing its nonnative synthesis pathway. To explore whether this synthetic biosynthesis...
PharmacologyLead Optimization of Dehydroemetine for Repositioned Use in MalariaDrug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel antimalarial treatments. The antiamoebic compound emetine dihydrochloride has been identified as a potent in vitro inhibitor of the multidrug-resistant strain K1 of Plasmodium falciparum (50% inhibitory concentration [IC50], 47 nM...
Mechanisms of Action: Physiological EffectsMechanism-of-Action Classification of Antibiotics by Global Transcriptome ProfilingAntimicrobial resistance (AMR) is an ever-growing public health problem worldwide. The low rate of antibiotic discovery coupled with the rapid spread of drug-resistant bacterial pathogens is causing a global health crisis. To facilitate the drug discovery processes, we present a large-scale study of reference antibiotic challenge bacterial transcriptome profiles, which included 37 antibiotics across 6 mechanisms of actions (MOAs) and...
Biologic Response ModifiersQuinazoline-Based Antivirulence Compounds Selectively Target Salmonella PhoP/PhoQ Signal Transduction SystemThe rapid emergence of multidrug resistance among bacterial pathogens has become a significant challenge to human health in our century. Therefore, development of next-generation antibacterial compounds is an urgent need. Two-component signal transduction systems (TCS) are stimulus-response coupling devices that allow bacteria to sense and elaborate adaptive responses to changing environmental conditions, including the challenges that...
Experimental TherapeuticsA Novel, Broad-Spectrum Antimicrobial Combination for the Treatment of Pseudomonas aeruginosa Corneal InfectionsBacterial keratitis causes significant blindness, yet antimicrobial resistance has rendered current treatments ineffective. Polymyxin B-trimethoprim (PT) plus rifampin has potent in vitro activity against Staphylococcus aureus and Pseudomonas aeruginosa, two important causes of keratitis....
PharmacologyTrypanosoma cruzi Phosphomannomutase and Guanosine Diphosphate-Mannose Pyrophosphorylase Ligandability AssessmentChagas’ disease, which is caused by the Trypanosoma cruzi parasite, has become a global health problem that is currently treated with poorly tolerated drugs that require prolonged dosing. Therefore, there is a clinical need for new therapeutic agents that can mitigate these issues. The phosphomannomutase (PMM) and GDP-mannose pyrophosphorylase (GDP-MP) enzymes form...
PharmacologyIdentification of Novel Trypanosoma cruzi Proteasome Inhibitors Using a Luminescence-Based High-Throughput Screening AssayChagas’ disease, caused by the protozoan parasite Trypanosoma cruzi, is a potentially life-threatening condition that has become a global issue. Current treatment is limited to two medicines that require prolonged dosing and are associated with multiple side effects, which often lead to treatment discontinuation and failure. One way to address these shortcomings is...
