Low-barrier hydrogen bond determines target-binding affinity and specificity of the antitubercular drug bedaquiline

The role of short strong hydrogen bonds (SSHB) in ligand-target binding remains largely unexplored, thereby hindering a potentially important avenue in the rational drug design. Here, we investigate the interaction between bedaquiline (Bq), a potent anti-tuberculosis drug, and the mycobacterial ATP synthase, to unravel the role of a specific hydrogen bond to a conserved acidic residue in the target affinity and specificity. Our ab initio molecular dynamics simulations reveal that this bond belongs to the SSHB category and accounts for a substantial fraction of the target binding energy. We also demonstrate that the presence of an extra acidic residue (D32), found exclusively in mycobacteria, cooperatively enhances the HB strength ensuring the specificity for the mycobacterial target. Consistently, we show that the removal of D32 markedly weakens the affinity, leading to Bq resistance associated with mutations of D32 to non-acidic residues. By designing simple Bq analogs, we then explore the possibility to overcome the resistance and potentially broaden the Bq antimicrobial spectrum by making the SSHB independent on the presence of the extra acidic residue.