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

Abstract

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 blaOXA‐51, blaOXA‐23, blaOXA‐58, and blaNDM genes, with over a third expressing 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 these carbapenemase genes resulted in sulbactam (SUL) resistance (MIC: 16–256 µg/ml) in all of the studied isolates. The efficacy of durlobactam (DUR), a novel β‐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 µM), OXA58‐DUR (−6.44 kcal/mol; 19.07 µM), and NDM‐DUR (−6.82 kcal/mol; 10.01 µM) complexes when compared with the conventional drugs avibactam and aztreonam. Stable interaction profiles of DUR with carbapenemases can possibly restore SUL activity against both PBP3WT and PBP3MTs. The study establishes the efficacy of the novel SUL–DUR combination as a successful treatment strategy in combating emerging XDR strains of A. baumannii.

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

“…The top-ranked complexes based on the lowest binding energies (highest affinities) were visualized using USCF Chimera (Pettersen et al, 2004) and Discovery Studio (Jejurikar and Rohane, 2021). The intermolecular interactions of the complexes were analyzed to determine the crucial residues of the target that can contribute to the drug binding (Basu et al, 2020;Miryala et al, 2021;Naha et al, 2021;Vasudevan et al, 2021).…”

“…From the drug affinity and structural impacts of nsSNPs, it can be hypothesized that the organism displays a tendency to accumulate clusters of nsSNPs in PBPs that will balance the overall thermodynamics and structural stability and, most importantly, reduce the antibiotic-binding affinity. Furthermore, since local free energy alterations contribute to the integrity of folded conformations, they directly affect the drug-binding affinity (Pires et al, 2014;Naha et al, 2021).…”

“…Standard antimicrobial susceptibility tests (AST) and wholegenome sequencing (WGS) were employed to identify β-lactamresistant S. pneumoniae isolates with altered PBPs. A structural analysis has been instrumental in understanding the impacts of underlying mutations on genomic imprints (Naha et al, 2021;Shankar et al, 2021). An in silico structural assessment comprehended the impact of individual nsSNPs in PBPs from cefotaxime/meropenem-resistant isolates.…”

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

“…Thereafter, the proteins were energy minimised by Powell's method with Tripos force field followed by Protomol generation. Hammerhead functional scorings determined the polar, crash, entropic, hydrophobic and repulsive properties to yield the docked score datasets [5 , 6] . The MDS analyses for 75 nanoseconds (ns) was performed for each of the best-docked complexes with GROMACS 2018.1 suite [7] .…”

Whole genome sequence of pan drug-resistant clinical isolate of Acinetobacter baumannii ST1890

“…Advances in whole-genome sequencing technology have facilitated bacterial whole-genome characterization, enhancing the ability to elucidate the antibiotic-resistant mechanism and pathogenesis in Acinetobacter baumannii [ 33 , 34 ]. However, data concerning genome analysis on colistin resistance of Acinetobacter baumannii isolated from Thailand is currently limited in the literature [ 35 ].…”