A novel approach to overcome multidrug resistance in Acinetobacter baumannii
Background
The ESKAPE bacteria (E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, and Enterobacter spp.) are responsible for threatening hospital infections.
Our goal is to develop inhibitors for A. baumannii ATP synthase, which would counter the drug resistance mechanism.
Methodology
The crystal structure of A. baumannii F0 complex of ATP synthase was used for virtual screening.
The binding pockets were deduced from literature data at the a/c subunit interfaces.
There are “lagging” and “leading” pockets named by their relative position during the protein functioning cycle.
The Drug-Target Interaction (DTI) model is used to select top 10% of compounds from the pre-processed 3,8M compounds library using the smart consensus function type.
The top 50K compoundsare subject to molecular docking with AI rescoring into each of the binding pockets independently.
Top 20% of compounds were selected by the smart consensus function of type 2 followed by the human triage.
122 final hit candidates were selected.
Bacterial growth assay was used to test the potency of selected compounds.
The antimicrobial effect of inhibitors (IC50) was determined.
Project workflow
Results
11 compounds out of 122 hit candidates were selected to start laboratory studies.
2 compounds were validated as hits.
The compound R00439183 demonstrated the IC50 of 12.5 M whereas compound R00676319 demonstrated the IC50 of 4 M.
Binding mode of R00439183 (left) and R00676319 (right). Green dashed lines indicate hydrogen bonds, crimson - hydrophobic interactions, orange - charge
Inhibition of A. baumannii culture growth by R00439183 (left) and by R00676319 (right)
