Biology subjects

Thekkiniath, J.

Publications and source records attributed to Thekkiniath, J..

3 recordsLinked to original sources

bioRxiv2024

Tetra hydroxy ethyl disulfate disodium: a novel non-resistant antibacterial chelating agent

Discovery of novel antibacterial drugs is urgently required as common antibiotics have numerous side effects and are becoming less effective due to antibiotic resistance occurrences. Developing a novel class of antibacterial compounds without inducing the prevalence of resistance when used repeatedly against bacterial pathogens is presumably one of the best approaches to overcome this problem. Tetra hydroxy ethyl disulfate disodium (THES) is a novel antibacterial agent, capable of disrupting cell activity without any need for drug influx. In this study, the molecular interaction between THES, Gram-positive, and Gram-negative bacteria was investigated. It was suggested that THES possessed the desirable characteristics of a non-resistant bacterial agent with bactericidal properties. Additionally, the non-resistant characteristics of THES were validated as a novel antibacterial agent. The unique feature of THES was the property of chelation with its strong binding ability to target ligands. This binding played a major role in bacterial peptidoglycan porosity enlargement, resulting in lysis and cell death. The bacterial cell membrane porosity enlargement was confirmed by Scanning Electron Microscopy, Transmission Electron Microscopy, as well as Atomic Force Microscopy. These findings were further supported by the results from in silico analysis which showed that THES formed favorable interactions with peptidoglycan with a binding affinity of -4.7 kcal/mol. The minimum inhibitory concentration value against multidrug-resistant (MDR) bacteria was notably low, between 0.05 - 0.1%. Furthermore, the analysis of resistance over a seven-month course showed that Staphylococcus aureus did not develop resistant characteristics to repeated treatment to THES treatment. This study has also shown that bactericidal characteristics can be easily manipulated and modified for more preferable antibacterial activities, whilst yielding desirable pharmacokinetic/pharmacodynamics (PK/PD) properties. There are several advantages of THES as compared to common antibiotics, including its flexibility in the killing capacity of different microbial strains. The simplicity, efficacy, and non-resistant properties of THES make it a promising drug candidate or compound to combat the outbreak of MDR bacteria in the future.

biochemistry↗

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

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↗