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

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Abstract
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-, 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 hydrophilic and “open” ansa-bridge nature whereas the C-type conformer is more lipophilic due to the presence of a “closed” ansa-bridge structure. Involvement of the lactam moiety of the ansa-bridge in intramolecular H-bonds within rifapentine and rifampicin implicates formation of a more hydrophilic A-type conformer. In contrast to rifampicin and rifapentine, for rifabutin and rifaximin "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 changing nature of bacteria cell membranes, especially those of Gram-negative strains and/or to efflux pump systems.
Funding Information
  • Deutscher Akademischer Austauschdienst (57314018)
  • Narodowe Centrum Nauki (2017/25/B/ST5/00291)

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