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

Abstract

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.