Are the physicochemical properties of antibacterial compounds really different from other drugs?
BACKGROUND
It is now widely recognized that there is an urgent need for new antibacterial drugs, with novel mechanisms of action, to combat the rise of multi-drug resistant bacteria. However, few new compounds are reaching the market. Antibacterial drug discovery projects often succeed in identifying potent molecules in biochemical assays but have been beset by difficulties in obtaining antibacterial activity. A commonly held view, based on analysis of marketed antibacterial compounds, is that antibacterial drugs possess very different physicochemical properties to other drugs, and that this profile is required for antibacterial activity.


RESULTS
We have re-examined this issue by performing a cheminformatics analysis of the literature data available in the ChEMBL database. The physicochemical properties of compounds with a recorded activity in an antibacterial assay were calculated and compared to two other datasets extracted from ChEMBL, marketed antibacterials and drugs marketed for other therapeutic indications. The chemical class of the compounds and Gram-negative/Gram-positive profile were also investigated. This analysis shows that compounds with antibacterial activity have physicochemical property profiles very similar to other drug classes.


CONCLUSIONS
The observation that many current antibacterial drugs lie in regions of physicochemical property space far from conventional small molecule therapeutics is correct. However, the inference that a compound must lie in one of these "outlier" regions in order to possess antibacterial activity is not supported by our analysis. Graphical abstract.
InhibOx Limited, Oxford Centre for Innovation, New Road, Oxford, OX1 1BY UK ; Centre for Molecular Medicine and Biobanking, University of Malta, Msida, MSD 2080 Malta.
Jean-Paul
JP
Ebejer
InhibOx Limited, Oxford Centre for Innovation, New Road, Oxford, OX1 1BY UK.
Michael H
MH
Charlton
InhibOx Limited, Oxford Centre for Innovation, New Road, Oxford, OX1 1BY UK ; University of Buckingham, Hunter Street, Buckingham, MK18 1EG UK.
Paul W
PW
Finn
Antibacterials; ChEMBL; Cheminformatics database analysis; Drug-like compounds; Molecular properties