Specific Interactions between Rifamycin Antibiotics and Water Influencing Ability To Overcome Natural Cell Barriers and the Range of Antibacterial Potency

Rifamycins are a group of macrocyclic
antibiotics mainly used for
the treatment of various bacterial infections including tuberculosis.
Spectroscopic studies of rifamycins evidence the formation of temperature-
and solvent-dependent equilibria between A-, B-, and C-type conformers
in solutions. The B- and C-type conformers of rifamycin antibiotics
are exclusively formed in the presence of water molecules. A- and
B-type conformers exhibit a hydrophilic and “open” ansa-bridge nature whereas the C-type conformer is more
lipophilic due to the presence of a “closed” ansa-bridge structure. The involvement of the lactam moiety
of the ansa-bridge in intramolecular H-bonds within
rifapentine and rifampicin implicates the formation of a more hydrophilic
A-type conformer. In contrast to rifampicin and rifapentine, for rifabutin
and rifaximin, the “free” lactam group enhances conformational
flexibility of the ansa-bridge, thereby enabling
interconversion between A- and C-type conformers. In turn, an equilibrium
between A- and C-type conformers for rifamycins improves their adaptation
to the changing nature of bacteria cell membranes, especially those
of Gram-negative strains and/or to efflux pump systems.