Latent tuberculosis and computational biology: A less-talked affair

Sarmah, Dipanka Tanu; Parveen, Rubi; Kundu, Jayendrajyoti; Chatterjee, Samrat

doi:10.1016/j.pbiomolbio.2023.02.002

Cited by 3 publications

(3 citation statements)

References 132 publications

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“…The objective of our QSAR model was to identify crucial molecular features of small-molecule modulators that strongly correlate with their inhibitory activity against Mtb β-CA, which might effectively halt the progression of TB and offer valuable insights for the design and discovery of anti-TB drugs. In this study, we propose a novel cheminformatics pipeline to generate multiple machine learning-assisted quantitative structural activity relationship (ML-QSAR) prediction models with diverse molecular features to explore the chemical space of Mtb β-CA inhibitors [22][23][24]. In this pursuit, we employed a random forest (RF) ML algorithm to generate each of our multidiverse molecular feature-based ML-QSAR models (PubChem fingerprints, substructure fingerprints, and 1D and 2D molecular descriptors).…”

mentioning

confidence: 99%

WITHDRAWN: Mechanistic modeling of Mycobacterium tuberculosis β-carbonic anhydrase inhibitors using integrated systems biology and the QSAR approach

Bhowmik,

Manaithiya,

Parkkinen

et al. 2024

Preprint

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Mycobacterium tuberculosis (Mtb) β-carbonic anhydrases (β-CAs) are crucial enzymes responsible for regulating pH by catalyzing the conversion of CO2 to HCO3-, which is essential for its survival in acidic environments in the host. By inhibiting Mtb β-CAs, we can potentially discover new targets for anti-tuberculosis drugs with a different mechanism of action than existing FDA-approved drugs. This is crucial since Mtb has demonstrated the ability to develop different degrees of resistance to current drugs over time. This study employed machine learning-assisted quantitative structural activity relationship (ML-QSAR) models utilizing PubChem fingerprints, substructure fingerprints, and 1D 2D molecular descriptors to decipher the structural insights underlying the Mtb β-CA inhibition mechanism among 267 molecules. The final models, based on a random forest (RF) ML algorithm, demonstrated robustness with correlation coefficients of 0.931, 0.9227, and 0.9447, respectively. The final predictive models were further developed as a user-friendly web application, Mtb-CA-pred (https://mtb-ca-pred.streamlit.app/), which was further used to screen an anti-TB compound library of 11,800 molecules. We obtained two lead molecules, F0804-1219 and F1092-1799, from the virtual screening study, which were further subjected to a mechanistic systems biology framework to elucidate their inhibition mechanism through different biological pathways against Mtb β-CAs. Experimental validation via the minimum duration for killing (MDK) assay confirmed the bactericidal effects of the two identified compounds against Mycobacterium marinum biofilms, aligning computational predictions with experimental outcomes in drug discovery. These findings underscore the efficacy of the identified compounds as potent anti-TB agents, bridging computational and experimental approaches in anti-TB drug development.

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confidence: 99%

WITHDRAWN: Mechanistic modeling of Mycobacterium tuberculosis β-carbonic anhydrase inhibitors using integrated systems biology and the QSAR approach

Bhowmik,

Manaithiya,

Parkkinen

et al. 2024

Preprint

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“…[1] As an air-borne pathogen, Mtb infects over a billion of the world population. [2] Although the majority of infected individuals are asymptomatic and ultimately clear of the latent infection, a substantial percentage remain infected for life. A subset of the latent tuberculosis will progress into an active disease, which results in a death toll of more than 1.5 million annually, explaining why it has become the leading cause of mortality.…”

Section: Introductionmentioning

confidence: 99%

“…Mycobacterium tuberculosis ( Mtb ), a slow growing pathogen infecting the lungs, represents the causative agent of tuberculosis (Tb) that has been a threat to mankind since early civilizations [1] . As an air‐borne pathogen, Mtb infects over a billion of the world population [2] . Although the majority of infected individuals are asymptomatic and ultimately clear of the latent infection, a substantial percentage remain infected for life.…”

Section: Introductionmentioning

confidence: 99%

Sulfoglycolipids and Related Analogues of Mycobacterium tuberculosis: Chemical Synthesis and Immunological Studies

Chiu,

Tan,

Mondal

et al. 2023

ChemMedChem

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Mycobacterium tuberculosis (Mtb) causes tuberculosis as one major threat to human health, which has been deteriorated owing to the emerging multidrug resistance. Mtb contains a complex lipophilic cell wall structure that is important for bacterial persistence. Among the lipid components, sulfoglycolipids (SGLs), known to induce immune cell responses, are composed of a trehalose core attached with a conserved sulfate group and 1−4 fatty acyl chains in an asymmetric pattern. At least one of these acyl chains is polymethylated with 3−12 methyl branches. Although Mtb SGL can be isolated from bacterial culture, resulting SGL is still a homologous mixture, impeding accurate research studies. This up‐to‐date review covers the chemical synthesis and immunological studies of Mtb SGLs and structural analogues, with an emphasis on the development of new glycosylation methods and the asymmetric synthesis of polymethylated scaffolds. Both are critical to advance further research on biological functions of these complicated SGLs.

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Visual evoked potential as an early assessment tool in ethambutol-induced toxic optic neuropathy during treatment of tuberculosis

Misra,

Sethi,

Singh

2024

IJCEO

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The objective of this study was to determine whether visual evoked potential (VEP) may be utilized as a screening tool for Ethambutol-induced toxic optic neuropathy (EITON) and whether discontinuing the use of Ethambutol will reverse the signs and symptoms of EITON in patients who are suffering from tuberculosis.Following receipt of authorization from the Institutional Ethics Committee to proceed with the present study, the study officially got underway. The World Health Organization recommended that forty people who had been diagnosed with tuberculosis get ethambutol medication for a period of six months at a dosage of 15-19 milligrams per kilogram of body weight. These patients were inspected both before and after receiving the treatment. Visual function tests and visual evoked potential (VEP) tests were administered to each patient to assess the visual pathway's condition.An irregular VEP pattern was seen in seven patients out of forty individuals, which accounts for 17.5% of the total. Among these seven patients, delayed P100 latency was observed in all seven patients (17.5%), and an aberrant amplitude difference was documented in one patient (2.5%). There were four patients (10%) who were found to have suboptimal visual acuity, and there were three patients (7.5%) who were found to have problems with their colour vision. An association between low visual acuity and increased P100 delay values was discovered in three out of seven cases. This was the case that was investigated. One patient's visual acuity and colour vision had decreased after two months of Ethambutol therapy, while three patients' visual acuity and colour vision had decreased within four to six months of medication. Due to the absence of abnormalities in the fundus, a diagnosis of retrobulbar optic neuritis was made in these four cases, constituting 10% of the total. There was a full reversal of P100 delay in three patients (43%) out of seven and a partial reversal in four (57%) out of seven.Our study demonstrates that even at the recommended doses of ethambutol, a timely and routinely performed pattern VEP can detect a significant proportion of cases of subclinical optic neuritis. Furthermore, it demonstrates that the signs and symptoms of ocular toxicity can be reversed in a significant number of these patients after the cessation of Ethambutol treatment.

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Latent tuberculosis and computational biology: A less-talked affair

Cited by 3 publications

References 132 publications

WITHDRAWN: Mechanistic modeling of Mycobacterium tuberculosis β-carbonic anhydrase inhibitors using integrated systems biology and the QSAR approach

WITHDRAWN: Mechanistic modeling of Mycobacterium tuberculosis β-carbonic anhydrase inhibitors using integrated systems biology and the QSAR approach

Sulfoglycolipids and Related Analogues of Mycobacterium tuberculosis: Chemical Synthesis and Immunological Studies

Visual evoked potential as an early assessment tool in ethambutol-induced toxic optic neuropathy during treatment of tuberculosis

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