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

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

Automated summary

The study identified the prevalence of carbapenemase genes in Indian isolates of Acinetobacter baumannii, leading to sulbactam resistance. In silico analysis showed that the novel beta-lactamase inhibitor durlobactam had higher binding affinities and lower inhibition constants with carbapenemases compared to conventional drugs, suggesting it could be an effective treatment strategy against XDR strains of A. baumannii.