Drug repurposing approach to target FtsZ cell division protein from Salmonella Typhi

Naz, Farah; Mashkoor, Muneera; Sharma, Priyanka; Haque, Anzarul; Kapil, Arti; Kumar, Manoj; Kaur, Punit; Samath, Ethayathulla Abdul

doi:10.1016/j.ijbiomac.2020.05.063

Cited by 14 publications

(3 citation statements)

References 48 publications

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“…The MIC values of ADMA in our work were observed to be 512 µgmL −1 and the zone of inhibition of 23.12mm at 5 µgmL −1 . The results are also in correlation with antibacterial activity against B. subtilis SBUG14 where ADMA gave a zone of inhibition of 3.5 mm at 100 µgmL −1 [ 64 ]. A team of researchers from AIIMS, New Delhi, India, in their work showed that amongst the FDA-approved drugs, benzethonium chloride gave a MIC value of 8 µgmL −1 for Salmonella Typhi (ATCC 19430), 1 µgmL −1 for Staphylococcus aureus (ATCC 43300) and 12 µgmL −1 for Escherichia coli (ATCC 25922) [ 65 ].…”

Section: Discussionmentioning

confidence: 92%

“…Agar well diffusion assay and macro broth dilution method were used to validating inhibitory action of Aphanorphine (5 µgmL −1 ) and ADMA (5 µgmL −1 ) along with methanolic extracts (100 µgmL −1 ) of Oscillatoria sp. against B. subtilis MTCC-441 [ 47 , 48 , 51 , 52 , 64 , 77 ]. Polymyxin B sulfate (5 µgmL −1 ) was used as a positive control, which is an antibiotic for treating various bacterial infections [ 77 ].…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of Filamentous Thermosensitive Mutant-Z Protein in Bacillus subtilis by Cyanobacterial Bioactive Compounds

et al. 2022

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Antibiotic resistance is one of the major growing concerns for public health. Conventional antibiotics act on a few predefined targets and, with time, several bacteria have developed resistance against a large number of antibiotics. The WHO has suggested that antibiotic resistance is at a crisis stage and identification of new antibiotics and targets could be the only approach to bridge the gap. Filamentous Temperature Sensitive-Mutant Z (Fts-Z) is one of the promising and less explored antibiotic targets. It is a highly conserved protein and plays a key role in bacterial cell division by introducing a cytokinetic Z-ring formation. In the present article, the potential of over 165 cyanobacterial compounds with reported antibiotic activity against the catalytic core domain in the Fts-Z protein of the Bacillus subtilis was studied. The identified cyanobacterial compounds were screened using the GLIDE module of Maestro v-2019-2 followed by 100-ns molecular dynamics (MD) simulation. Ranking of the potential compound was performed using dock score and MMGBSA based free energy. The study reported that the docking score of aphanorphine (−6.010 Kcalmol−1) and alpha-dimorphecolic acid (ADMA) (−6.574 Kcalmol−1) showed significant role with respect to the reported potential inhibitor PC190723 (−4.135 Kcalmol−1). A 100 ns MD simulation infers that Fts-Z ADMA complex has a stable conformation throughout the progress of the simulation. Both the compounds, i.e., ADMA and Aphanorphine, were further considered for In-vitro validation by performing anti-bacterial studies against B. subtilis by agar well diffusion method. The results obtained through In-vitro studies confirm that ADMA, a small molecule of cyanobacterial origin, is a potential compound with an antibacterial activity that may act by inhibiting the novel target Fts-Z and could be a great drug candidate for antibiotic development.

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Section: Discussionmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Inhibition of Filamentous Thermosensitive Mutant-Z Protein in Bacillus subtilis by Cyanobacterial Bioactive Compounds

et al. 2022

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“…The best model for each individual species was selected based on Levitt-Gerstein (LG) score (Levitt and Gerstein 1998) using the neural network-based method and ProQ server (https://proq.bioinfo.se/ProQ/ProQ.html). The chosen model of each species were re ned by energy minimization using previously reported parameters (Yadav et al 2019;Naz et al 2020). The stereochemical quality of the 16 models was evaluated by the PROCHECK program (Laskowski et al 1993) and ERRAT server (Colovos and Yeates 1993).…”

Section: Homology Modellingmentioning

confidence: 99%

Structural analysis of COVID-19 spike protein in recognizing the ACE2 receptor of different mammalian species and its susceptibility to viral infection.

Koley

Madaan

Chowdhury

et al. 2020

Preprint

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The pandemic COVID-19 caused by a novel coronavirus SARS-CoV-2 spread worldwide as a new public health emergency. The SARS-CoV-2 infects humans by binding to glycosylated ACE2 receptor present in the inner lining of the lungs, heart, intestine and kidney. The COVID spike 2 protein recognizes the ACE2 receptor at the N-terminal helices of the metalloprotease domain. The residues Gln24, Thr27, Lys31, His34, Glu37, Asp38, Tyr41, Gln42 from helix α1; Leu79, Met82, Tyr83 from helix α2 and Gln325, Glu329, Asn330, Lys353 from loop connecting β4 and β5 strands form a concave surface surrounded by four glycosylation sites Asn53, Asn90, Asn103 and Asn322 form interactions with the spike protein. However, no significant data on the susceptibility of animals for infection or transmission. Therefore, we performed the comparative protein-protein docking analysis using the crystal structure of spike protein and homology models of the ACE2 receptor from 16 commonly found mammalian species to understand the potential mode of spike binding. Our comprehensive sequence and structure-based interaction analysis revealed the natural substitution of amino acid residues Gln24, His34, Phe40 and Met82 in the N-terminal α1 and α2 helices results in loss of crucial network of hydrogen-bonded and hydrophobic interactions with spike 2 RBD domain. Besides, the absence of N-linked glycosylation site Asn103 in other mammals further reduces the binding affinity between spike and ACE2 receptor. Hence, these changes explain the differences in the susceptibility and host pathogenesis in other mammalian species.

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The Combination of Membrane Disruption and FtsZ Targeting by a Chemotherapeutic Hydrogel Synergistically Combats Pathogens Infections

Wei,

Guo,

Geng

et al. 2024

Adv Healthcare Materials

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The emergence of multidrug‐resistant (MDR) bacteria poses a significant challenge to global health. Due to a shortage of antibiotics, alternative therapeutic strategies are urgently needed. Unfortunately, colistin, the last‐resort antibiotic, has unavoidable nephrotoxicity and hepatotoxicity, and its single killing mechanism is prone to drug resistance. To address this challenge, we propose a promising combinatorial approach that includes colistin, a membrane‐disrupting antimicrobial agent, and chelerythrine (CHE), a FtsZ protein inhibitor. This approach significantly reduces antibiotic dose and development of resistance, leading to almost complete inactivation of MDR pathogens in vitro. To address solubility issues and ensure transport, we used the antimicrobial hydrogel system LNP‐CHE‐CST@hydrogel, which induced reactive oxygen species (ROS) and apoptosis‐like cell death by targeting the FtsZ protein. In an in vivo mouse skin infection model, the combination therapy effectively eliminated MDR bacteria within 24 hours, as monitored by fluorescence tracking. Our findings demonstrate a promising approach for developing multifunctional hydrogels to combat MDR bacterial infections.This article is protected by copyright. All rights reserved

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Drug repurposing approach to target FtsZ cell division protein from Salmonella Typhi

Cited by 14 publications

References 48 publications

Inhibition of Filamentous Thermosensitive Mutant-Z Protein in Bacillus subtilis by Cyanobacterial Bioactive Compounds

Inhibition of Filamentous Thermosensitive Mutant-Z Protein in Bacillus subtilis by Cyanobacterial Bioactive Compounds

Structural analysis of COVID-19 spike protein in recognizing the ACE2 receptor of different mammalian species and its susceptibility to viral infection.

The Combination of Membrane Disruption and FtsZ Targeting by a Chemotherapeutic Hydrogel Synergistically Combats Pathogens Infections

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