Identification of a potential inhibitor for New Delhi metallo-β-lactamase 1 (NDM-1) from FDA approved chemical library- a drug repurposing approach to combat carbapenem resistance DOI

S. Shailaja,

N Harshitha,

Aneesa Fasim

et al.

Journal of Biomolecular Structure and Dynamics, Journal Year: 2022, Volume and Issue: 41(16), P. 7700 - 7711

Published: Sept. 27, 2022

Superbugs producing New Delhi metallo-β-lactamase 1 (NDM-1) enzyme is a growing crisis, that adversely affecting the global health care system. NDM-1 empowers bacteria to inactivate entire arsenal of β-lactam antibiotics including carbapenem (the last resort antibiotic) and remains ineffective all available β lactamase inhibitors used in clinics. Limited therapeutic option for rapidly disseminating makes it imperative identify potential inhibitor enzyme. With drug repurposing approach, this study, we virtual screening Food Drug Administration (FDA) approved chemical library (ZINC12 database) captured 'adapalene' (FDA drug) as potent candidate Active site docking with NDM-1, showed adapalene binding energy -9.21 kcal/mol interacting key amino acid residues (Asp124, His122, His189, His250, Cys208) active NDM-1. Further, molecular dynamic simulation docked at 100 ns displayed stable conformation dynamic, relative RMSD RMSF acceptable range. Subsequently, vitro assays using recombinant protein demonstrated inhibition by adapalene. combination plus meropenem (carbapenem synergistic effect against (meropenem) resistant clinical isolates (Escherichia coli Klebsiella pneumoniae). Overall, our data indicated can be contribute development suitable adjuvant save activity antibiotic infections caused positive gram-negative bacteria. Communicated Ramaswamy H. Sarma.

Language: Английский

Emergence of Meropenem Resistance Among Cefotaxime Non-susceptible Streptococcus pneumoniae: Evidence and Challenges DOI Creative Commons

Rosemol Varghese,

Soumya Basu,

Ayyanraj Neeravi

et al.

Frontiers in Microbiology, Journal Year: 2022, Volume and Issue: 12

Published: Feb. 3, 2022

The principal causative agent of acute bacterial meningitis (ABM) in children and the elderly is Streptococcus pneumoniae, with a widespread increase penicillin resistance. Resistance due to non-synonymous single-nucleotide polymorphisms (nsSNPs) that alter penicillin-binding proteins (PBPs), targets for all β-lactam drugs. Hence, resistance against one antibiotic may positively select another. Since meropenem an alternative cefotaxime meningeal infections, we aim identify whether nsSNPs PBPs causing can decrease pneumococcal susceptibility meropenem. Comparison between cefotaxime-resistant Indian (n = 33) global isolates 28) revealed PBP1A alone elevated minimal inhibitory concentrations (MICs) 0.12 μg/ml, both PBP2X 2B combined increases MIC ≥ 0.25 μg/ml. Molecular docking confirmed PBP drug binding affinity nsSNPs, thereby increasing inhibition potential values, leading Structural dynamics thermodynamic stability pattern as result mutations further depicted accumulation certain functional domains reduced without majorly affecting overall proteins. Restricting usage promoting combination therapy antibiotics having non-PBPs treat non-susceptible S. pneumoniae prevent selection

Language: Английский

Citations

35
Network metrics, structural dynamics and density functional theory calculations identified a novel Ursodeoxycholic Acid derivative against therapeutic target Parkin for Parkinson's disease DOI Creative Commons
Aniket Naha, Sanjukta Banerjee, Reetika Debroy

et al.

Computational and Structural Biotechnology Journal, Journal Year: 2022, Volume and Issue: 20, P. 4271 - 4287

Published: Jan. 1, 2022

Parkinson's disease (PD) has been designated as one of the priority neurodegenerative disorders worldwide. Although diagnostic biomarkers have identified, early onset detection and targeted therapy are still limited. An integrated systems structural biology approach were adopted to identify therapeutic targets for PD. From a set 49 PD associated genes, densely connected interactome was constructed. Based on centrality indices, degree interaction functional enrichments, LRRK2, PARK2, PARK7, PINK1 SNCA identified hub-genes. PARK2 (Parkin) finalized potent theranostic candidate marker due its strong association (score >0.99) with α-synuclein (SNCA), which directly regulates progression. Besides, modeling validation Parkin structure, an extensive virtual-screening revealed small (commercially available) inhibitors against Parkin. Molecule-258 (ZINC5022267) selected based pharmacokinetic profiles, Density Functional Theory (DFT) energy calculations (ΔE=6.93eV) high binding affinity (Binding energy=-6.57±0.1kcal/mol; Inhibition constant=15.35µM) Molecular dynamics simulation protein-inhibitor complexes further strengthened propositions stable trajectories (low fluctuations), hydrogen bonding patterns interactive energies (>0kJ/mol). Our study encourages experimental validations novel drug prevent auto-inhibition mediated ubiquitination in

Language: Английский

Citations

30
Non-steroidal anti-inflammatory drugs ketorolac and etodolac can augment the treatment against pneumococcal meningitis by targeting penicillin-binding proteins DOI
Soumya Basu,

Rosemol Varghese,

Reetika Debroy

et al.

Microbial Pathogenesis, Journal Year: 2022, Volume and Issue: 170, P. 105694 - 105694

Published: July 31, 2022

Language: Английский

Citations

23
Genome sequencing and molecular characterisation of XDR Acinetobacter baumannii reveal complexities in resistance: Novel combination of sulbactam–durlobactam holds promise for therapeutic intervention DOI
Aniket Naha, Saranya Vijayakumar,

Binesh Lal

et al.

Journal of Cellular Biochemistry, Journal Year: 2021, Volume and Issue: 122(12), P. 1946 - 1957

Published: Oct. 1, 2021

Abstract Emerging nosocomial strains of Acinetobacter baumannii are recent concern as they expressing extensive drug resistance (XDR). Using whole‐genome sequencing and molecular characterisation analysis, the current study reveals presence carbapenemase genes in 92.86% studied Indian isolates. These included bla OXA‐51 , OXA‐23 OXA‐58 NDM genes, with over a third dual genes. As per MLST scheme, IC2 Oxf /CC2 Pas was predominant clone, 57.14% isolates belonging to this lineage. The these resulted sulbactam (SUL) (MIC: 16–256 µg/ml) all efficacy durlobactam (DUR), novel β‐lactamase inhibitor that also inhibits PBP2 assessed through silico intermolecular interaction analysis. Several nonsynonymous single nucleotide polymorphisms were identified (G264S, I108V, S259T) PBP3 (A515V, T526S) sequences. Minimal variations recorded protein backbone dynamics active‐site motifs wild‐type mutants, which correlated negligible binding energy fluctuations for PBP3‐SUL (−5.85 ± 0.04 kcal/mol) PBP2‐DUR (−5.16 0.66 complexes. Furthermore, higher affinities low inhibition constants noted OXA23‐DUR (−7.36 kcal/mol; 4.01 µM), OXA58‐DUR (−6.44 19.07 NDM‐DUR (−6.82 10.01 µM) complexes when compared conventional drugs avibactam aztreonam. Stable profiles DUR carbapenemases can possibly restore SUL activity against both WT MTs . establishes SUL–DUR combination successful treatment strategy combating emerging XDR A.

Language: Английский

Citations

27
Designing Anti-Microbial Peptides Against Major β-Lactamase Enzymes in Clinically Important Gram-Negative Bacterial Pathogens: An In-Silico Study DOI
Soumya Basu, Sahil Mandar Joshi, Sudha Ramaiah

et al.

Probiotics and Antimicrobial Proteins, Journal Year: 2022, Volume and Issue: 14(2), P. 263 - 276

Published: Feb. 21, 2022

Language: Английский

Citations

19
Datasets comprising the quality validations of simulated protein-ligand complexes and SYBYL docking scores of bioactive natural compounds as inhibitors of Mycobacterium tuberculosis protein-targets DOI Creative Commons
Sravan Kumar Miryala, Soumya Basu, Aniket Naha

et al.

Data in Brief, Journal Year: 2022, Volume and Issue: 42, P. 108146 - 108146

Published: April 10, 2022

Docking scores and simulation parameters to study the potency of natural compounds against protein targets in Mycobacterium tuberculosis (Mtb) were retrieved through molecular docking in-silico structural investigation. The datasets comprised 15 compounds, seven conventional anti-tuberculosis (anti-TB) drugs their corresponding Mtb target proteins. actively involved translation mechanism, nucleic acid metabolism membrane integrity. Standard screening stereochemical optimizations adopted generate 3D structures ligands prior docking. Force-field integration energy minimization further employed obtain proteins ideal geometry. Surflex-dock algorithm using Hammerhead scoring functions used finally produce between each ligand(s). best-docked complexes selected for studies subjected topology adjustments, charge neutralizations, solvation equilibrations (temperature, volume pressure). protein-ligand dynamics parameter files have been provided. trajectories simulated such as density, pressure temperature generated with integrated tools suite. can be useful computational medicine researchers find therapeutic leads relevant chemical behaviours a specific class biological systems. Structural provided set standard values that utilised design experiments regarding similar macromolecular interactions.

Language: Английский

Citations

15
Structural chemistry and molecular-level interactome reveals histidine kinase EvgS to subvert both antimicrobial resistance and virulence in Shigella flexneri 2a str. 301 DOI
Aniket Naha, Sudha Ramaiah

3 Biotech, Journal Year: 2022, Volume and Issue: 12(10)

Published: Sept. 3, 2022

Language: Английский

Citations

15
Structure-based screening of natural product libraries in search of potential antiviral drug-leads as first-line treatment to COVID-19 infection DOI
S.J. Aditya Rao, Nandini P. Shetty

Microbial Pathogenesis, Journal Year: 2022, Volume and Issue: 165, P. 105497 - 105497

Published: March 22, 2022

Language: Английский

Citations

13
Emergence of sulphonamide resistance in azithromycin-resistant pediatric strains of Salmonella Typhi and Paratyphi A: A genomics insight DOI
Hithesh Kumar, Anand Manoharan, Anand Anbarasu

et al.

Gene, Journal Year: 2022, Volume and Issue: 851, P. 146995 - 146995

Published: Oct. 22, 2022

Language: Английский

Citations

11
Novel Antimicrobial Peptide SAAP Mutant as a Better Adjuvant to Sulbactam-Based Treatments Against Clinical Strains of XDR Acinetobacter baumannii DOI
Aniket Naha, Sudha Ramaiah

Probiotics and Antimicrobial Proteins, Journal Year: 2023, Volume and Issue: 16(2), P. 459 - 473

Published: March 27, 2023

Language: Английский

Citations

6