Biology subjects

Vydyam, P.

Publications and source records attributed to Vydyam, P..

9 recordsLinked to original sources

bioRxiv2026

Evaluating Acridones as Novel Therapeutics for Human Babesiosis

BackgroundHuman babesiosis is an emerging tick-borne disease caused by Babesia parasites, most notably Babesia microti and Babesia duncani in North America and Babesia divergens in Europe. Infections can be severe, persistent, or relapse despite treatment, and current therapeutic options remain limited, underscoring the urgent need for new and effective treatment options. MethodsAcridone derivatives, originally developed as potent antimalarial agents against multiple life cycle stages of the malaria parasites, were evaluated for their antibabesial activity using continuous in vitro culture systems of B. duncani and B. divergens. Lead candidates were assessed for selectivity against human cell lines to establish preliminary safety profiles, and select compounds were further advanced into preliminary in vivo efficacy studies using murine models of B. duncani and B. microti babesiosis to assess their therapeutic potential. ResultsNine prioritized acridone derivatives demonstrated potent in vitro activity against both B. duncani and B. divergens, accompanied by favorable selectivity indices relative to human cell lines. However, in vivo evaluation of representative compounds did not achieve parasite clearance in murine models. Structure-activity relationship (SAR) analyses highlighted key structural features that are critical for maintaining antibabesial potency and offer guidance for further lead optimization. ConclusionsAcridone derivatives show strong in vitro antibabesial activity and represent promising lead chemotypes for therapeutic development. To advance these candidates, future studies focused on optimizing their pharmacokinetic properties, improving in vivo efficacy, and evaluating synergistic combination regimens will be essential for progressing toward effective treatments for human babesiosis.

microbiology↗

bioRxiv2024

In Vitro Efficacy of Next Generation Dihydrotriazines and Biguanides Against Babesiosis and Malaria Parasites

Babesia and Plasmodium pathogens, the causative agents of babesiosis and malaria, are vector-borne intraerythrocytic protozoan parasites, posing significant threats to both human and animal health. The widespread resistance exhibited by these pathogens to various classes of antiparasitic drugs underscores the need for the development of novel and more effective therapeutics strategies. Antifolates have long been recognized as attractive antiparasitic drugs as they target the folate pathway, which is essential for the biosynthesis of purines and pyrimidines, and thus are vital for the survival and proliferation of protozoan parasites. More efficacious and safer analogs within this class are needed to overcome challenges due to resistance to commonly used antifolates such as the aminopyrimidine, pyrimethamine, and to address liabilities associated with the dihydrotriazines, WR99210 and JPC-2067. Here we utilized an in vitro culture condition suitable for continuous propagation of B. duncani, B. divergens, B. MO1 and P. falciparum in human erythrocytes to screen a library of 51 dihydrotriazines and 28 biguanides for their efficacy in vitro and to compare their potency and therapeutic indices across different species and isolates. We identified nine analogs that inhibit the growth of all species, including the P. falciparum pyrimethamine-resistant strain HB3 with IC50 values below 10 nM and demonstrated excellent therapeutic indices. These compounds hold substantial promise as lead antifolates for further development as broad-spectrum antiparasitic drugs.

microbiology↗

bioRxiv2024

Multiomics analysis reveals B. MO1 as a distinct Babesia species and provides insights into its evolution and virulence.

Babesiosis, caused by protozoan parasites of the genus Babesia, is an emerging tick-borne disease of significance for both human and animal health. Babesia parasites infect erythrocytes of vertebrate hosts where they develop and multiply rapidly to cause the pathological symptoms associated with the disease. The identification of various Babesia species underscores the ongoing risk of new zoonotic pathogens capable of infecting humans, a concern amplified by anthropogenic activities and environmental shifts impacting the distribution and transmission dynamics of parasites, their vectors, and reservoir hosts. One such species, Babesia MO1, previously implicated in severe cases of human babesiosis in the midwestern United States, was initially considered closely related to B. divergens, the predominant agent of human babesiosis in Europe. Yet, uncertainties persist regarding whether these pathogens represent distinct variants of the same species or are entirely separate species. We show that although both B. MO1 and B. divergens share similar genome sizes, comprising three nuclear chromosomes, one linear mitochondrial chromosome, and one circular apicoplast chromosome, major differences exist in terms of genomic sequence divergence, gene functions, transcription profiles, replication rates and susceptibility to antiparasitic drugs. Furthermore, both pathogens have evolved distinct classes of multigene families, crucial for their pathogenicity and adaptation to specific mammalian hosts. Leveraging genomic information for B. MO1, B. divergens, and other members of the Babesiidae family within Apicomplexa provides valuable insights into the evolution, diversity, and virulence of these parasites. This knowledge serves as a critical tool in preemptively addressing the emergence and rapid transmission of more virulent strains.

microbiology↗

bioRxiv2023

Vitamin B5 Metabolism is Essential for Vacuolar and Mitochondrial Integrity and Xenobiotic Detoxification in Fungi

Fungal infections, a leading cause of mortality among eukaryotic pathogens, pose a growing global health threat due to the rise of drug-resistant strains. New therapeutic strategies are urgently needed to combat this challenge. The PCA pathway for biosynthesis of Co-enzyme A (CoA) and Acetyl-CoA (AcCoA) from vitamin B5 (pantothenic acid) has been validated as an excellent target for the development of new antimicrobials against fungi and protozoa. The pathway regulates key cellular processes including metabolism of fatty acids, amino acids, sterols, and heme. In this study, we provide genetic evidence that disruption of the PCA pathway results in a significant alteration in the susceptibility of fungi to a wide range of xenobiotics, including clinically approved antifungal drugs through alteration of vacuolar integrity and drug detoxification. The drug potentiation-mediated by genetic regulation of genes in the PCA pathway could be recapitulated using the pantazine analog PZ-2891 as well as the celecoxib derivative, AR-12 through inhibition of fungal AcCoA synthase activity. Collectively, the data validate the PCA pathway as a suitable target for enhancing the efficacy and safety of current antifungal therapies.

microbiology↗

bioRxiv2023

A Potent Kalihinol Analogue Disrupts Apicoplast Function and Vesicular Trafficking in P. falciparum Malaria.

Here we report the discovery of MED6-189, a new analogue of the kalihinol family of isocyanoterpene (ICT) natural products. MED6-189 is effective against drug-sensitive and-resistant P. falciparum strains blocking both intraerythrocytic asexual replication and sexual differentiation. This compound was also effective against P. knowlesi and P. cynomolgi. In vivo efficacy studies using a humanized mouse model of malaria confirms strong efficacy of the compound in animals with no apparent hemolytic activity or apparent toxicity. Complementary chemical biology, molecular biology, genomics and cell biological analyses revealed that MED6-189 primarily targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses in P. falciparum revealed that a mutation in PfSec13, which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. The high potency of MED6-189 in vitro and in vivo, its broad range of efficacy, excellent therapeutic profile, and unique mode of action make it an excellent addition to the antimalarial drug pipeline. Editors SummaryHere we report the mode of action and mechanism of resistance of a pan-antimalarial agent, MED6-189, which disrupts apicoplast function and vesicular trafficking in P. falciparum.

microbiology↗

bioRxiv2022

Decoding The Nuclear Genome of The Human Pathogen Babesia duncani Shed Light on its Virulence, Drug Susceptibility and Evolution among Apicomplexa

Babesia species are tick-transmitted apicomplexan pathogens and the causative agents of babesiosis, a malaria-like disease of major medical and veterinary importance. Of the different species of Babesia reported so far, Babesia duncani causes severe to lethal infection in patients. Despite the highly virulent nature of this parasite and the risk it may pose as an emerging pathogen, little is known about its biology, metabolic requirements, and pathogenesis. B. duncani is unique among apicomplexan parasites that infect red blood cells in that it can be continuously cultured in vitro in human erythrocytes but can also infect mice leading to fulminant babesiosis infection and death. Here we have taken advantage of the recent advances in the propagation of this parasite in vitro and in vivo to conduct detailed molecular, genomic and transcriptomic analyses and to gain insights into its biology. We report the assembly, 3D structure, and annotation of the nuclear genome of this parasite as well as its transcriptomic profile and an atlas of its metabolism during its intraerythrocytic life cycle. Detailed examination of the B. duncani genome and comparative genomic analyses identified new classes of candidate virulence factors, suitable antigens for diagnosis of active infection, and several attractive drug targets. Translational analyses and efficacy studies identified highly potent inhibitors of B. duncani thus enriching the pipeline of small molecules that could be developed as effective therapies for the treatment of human babesiosis.

microbiology↗

bioRxiv2021

Babesia duncani as a model organism to study the development, virulence and drug susceptibility of intraerythrocytic parasites in vitro and in vivo

Hematozoa are a subclass of protozoan parasites that invade and develop within vertebrate red blood cells to cause the pathological symptoms associated with diseases of both medical and veterinary importance such as malaria and babesiosis. A major limitation in the study of the most prominent hematozoa, Plasmodium spp, the causative agents of malaria, is the lack of a broadly accessible mouse model to evaluate parasite infection in vivo as is the case for P. falciparum or altogether the lack of an in vitro culture and mouse models as is the case for P. vivax, P. malariae and P. ovale. Similarly, no in vitro culture system exists for Babesia microti, the predominant agent of human babesiosis. In this study, we show that human red blood cells infected with the human pathogen Babesia duncani continuously propagated in culture, as well as merozoites purified from parasite cultures, can cause lethal infection in immunocompetent C3H/HeJ mice. Furthermore, highly reproducible parasitemia and survival outcomes were established using specific parasite loads and different mouse genetic backgrounds. Using the combined in culture-in mouse (ICIM) model of B. duncani infection, we demonstrate that current recommended combination therapies for the treatment of human babesiosis, while synergistic in cell culture, have weak potency in vitro and failed to clear infection or prevent death in mice. Interestingly, using the ICIM model, we identified two new endochin-like quinolone prodrugs, ELQ-331 and ELQ-468, that alone or in combination with atovaquone are highly efficacious against B. duncani and B. microti. The novelty, ease of use and scalability of the B. duncani ICIM dual model make it an ideal system to study intraerythrocytic parasitism by protozoa, unravel the molecular mechanisms underlying parasite virulence and pathogenesis, and accelerate the development of innovative therapeutic strategies that could be translated to unculturable parasites and important pathogens for which an animal model is lacking. Author SummaryUse of model organisms is vital to the understanding of virulence and pathogenesis of a large number of human and animal pathogens. In case of hematozoan parasites that invade and develop within vertebrate erythrocytes, the studies are challenging because of the dearth of small animal model systems and the lack of continuous parasite growth in in vitro culture conditions. Here, we report a small animal model of lethal infection of Babesia duncani, one of the causative agents of human babesiosis. We show that in vitro cultured parasites and as well as parasites propagated in vivo can establish highly reproducible parasitemia which is dependent on the parasite load and also defined by different mouse genetic backgrounds. We further use this combined in culture-in mouse (ICIM) model of B. duncani infection to demonstrate the anti-babesial efficacy of two novel endochin like quinoline compounds. We propose that this ICIM dual model of B. duncani is an ideal system to get insights into protozoan intraerythrocytic parasitism, virulence, pathogenesis, and therapeutics and will open the vista to other important pathogens which are unculturable or lack an animal model.

microbiology↗

bioRxiv2021

A Chimeric Peptide Inhibits Red Blood Cell Invasion by Plasmodium falciparum with Hundredfold Increased Efficacy

Inhibition of tight junction formation between two malaria parasite proteins, apical membrane antigen 1 and rhoptry neck protein 2, crucial for red blood cell invasion, prevents the disease progression. In this work, we have utilized a unique approach to design a chimeric peptide, prepared by fusion of the best features of two peptide inhibitors, that has displayed parasite growth inhibition, in-vitro, with nanomolar IC50, which is hundredfold better than any of its parent peptides. Further, to gain structural insights, we computationally modeled the hybrid peptide on its receptor.

biochemistry↗

bioRxiv2021

Effective Therapy Targeting Cytochrome bc1 Prevents Babesia Erythrocytic Development and Protects from Lethal Infection

Targeting conserved metabolic processes that are essential for viability of pathogens, such as Plasmodium and Babesia that cause blood-borne diseases, is an effective strategy to eliminate malaria and babesiosis infections with no recrudescence. One interesting target is the mitochondrial cytochrome bc1 complex, which could be inhibited by drugs such as endochin-like quinolones (ELQ) and atovaquone. We used the tick-transmitted and culturable blood-borne pathogen Babesia duncani to evaluate the structure-activity relationship, safety, efficacy and mode of action of ELQs. We identified a potent and highly selective ELQ prodrug (ELQ-502), which alone or in combination with atovaquone eliminates B. microti and B. duncani infections in vitro and in mouse models of parasitemia and lethal infection. The strong efficacy at low dose, excellent safety, bioavailability and long half-life of this experimental therapy makes it an ideal clinical candidate for the treatment of human infections caused by Babesia and its closely related apicomplexan parasites.

microbiology↗