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Anbarasu, A.

Publications and source records attributed to Anbarasu, A..

2 recordsLinked to original sources
bioRxiv2021

Genome sequencing and molecular characterisation of XDR Acinetobacter baumannii reveal complexities in resistance: Novel combination of Sulbactam-Durlobactam holds promise for therapeutic intervention

Acinetobacter baumannii is an emerging nosocomial strain expressing extensive drug resistance (XDR). Whole-genome sequencing and molecular characterisation analysis revealed the presence of carbapenemase in 92.86% of studied Indian isolates having blaOXA-51, blaOXA-23, blaOXA-58, and blaNDM genes, with a few evidences of dual carbapenemase genes. As per the MLST scheme, IC2Oxf/CC2Pas was the predominant clone, with 57.14% isolates belonging to this lineage. The presence of {beta}-lactamases has rendered sulbactam (SUL) resistance (MIC: 16-256{micro}g/ml) in all the studied isolates. The efficacy of novel durlobactam (DUR) in inhibiting {beta}-lactamases and PBP2 was assessed through in-silico inter-molecular interaction analysis. Several non-synonymous single nucleotide polymorphisms (nsSNPs) were identified in PBP2 (G264S, I108V, S259T) and PBP3 (A515V, T526S) sequences. Minimal variations were recorded in the protein-backbone dynamics in active-site motifs of wild-type (WT) and mutants (MT), which correlated with the negligible binding energy fluctuations for PBP3-SUL (-5.85{+/-}0.04Kcal/mol) and PBP2-DUR (-5.16{+/-}0.66Kcal/mol) complexes. Furthermore, stronger binding affinities and low inhibition constants were noted in DUR complexed with OXA23 (-7.36Kcal/mol; 4.01{micro}M), OXA58 (-6.44Kcal/mol; 19.07{micro}M) and NDM (-6.82Kcal/mol; 10.01{micro}M) when compared with conventional drugs avibactam and aztreonam. Stable interaction profiles of DUR, can possibly restore SUL activity against both PBP3WT and PBP3MTs. The study establishes the efficacy of novel SUL-DUR combination as a successful treatment strategy to combat emerging XDR strains.

microbiology↗
bioRxiv2021

Identification of potential carboxylic acid-containing drug candidate to design novel competitive NDM inhibitors: An in-silico approach comprising combined virtual screening and molecular dynamics simulation

Metallo-{beta}-lactamases (MBLs) producing bacteria especially the ones with New Delhi metallo-beta-lactamase-1 (NDM-1) and its variants can potentially hydrolyse all the major {beta}-lactam antibiotics, ultimately escalating anti-microbial resistance world-wide. There is a dearth of approved inhibitors to combat NDM and other MBLs producing bacteria. Hence we focussed to find novel inhibitor(s) in-silico which can potentially suppress the activity of NDM/ MBLs. 2400 compounds were virtually screened to identify a promising carboxylic acid-containing compound (CID-53986787) analogous to NDM antagonist Captopril. Our lead compound can bind adjacent to the active site zinc ions (Zn1 and Zn2) in all highly resistant NDM variants. CID-53986787 possesses ~5-8% higher binding affinity than Captopril, exhibiting molecular interactions with crucial residues that can destabilize the hydrolytic activity of NDM. CID-53986787 was virtually evaluated to ascertain its safe pharmacological/ toxicity profile. Molecular dynamics simulation studies elucidated its stable interaction with the target protein (NDM-1).

bioinformatics↗