Antimicrobial activity of triphenylphosphonium (TPP) conjugates of alkynyl-substituted nucleic bases and their analogues.

Twenty triphenylphosphonium (TPP) conjugates in which 1-alkynyl-substituted nucleic bases (uracil, thymine) and their analogues (6-methyluracil, quinazoline-2,4-dione) were connected to the TPP cation via an octyl or decyl linker were synthesized. In vitro evaluation of their antibacterial activity against five Gram-positive bacteria, two Gram-negative bacteria and fungus C. albicans revealed six lead compounds which exhibited high bacteriostatic activity (MIC 0.2-0.9 μM) against Gram-positive bacteria S. aureus, B. cereus, E. faecalis, as well as MRSA strains. These lead compounds are TPP-conjugates in which 1-alkynylquinazoline-2,4-dione moiety is bound to the TPP cation via the decyl (4 d, 4 f) or octyl (4e) linker and biscationic TPP-conjugates in which two TPP cations are attached to the N-1 and N-3 atoms of 5-alkynylquinazoline-2,4-dione moiety via the decyl (5 d, 5 f) or octyl (5e) linkers. Biscations 5 d and 5e showed high in vitro bacteriostatic and bactericidal activity (MIC/MBC 0.2-7.8 μM) against Gram-negative bacteria E. coli and P. aeruginosa. In addition, biscations 5 d and 5 f exhibited noticeable in vitro fungistatic and fungicidal activity against fungus C. albicans. Using colorimetric and fluorimetric methods, it was found that all lead compounds at concentrations corresponding to the MIC and MBC values caused cytoplasmic membrane damage and depolarization, without violating the integrity of the S. aureus cell wall. In addition, all lead compounds inhibited the formation of S. aureus biofilm by 80-100% at concentrations close to the MBC value (about 0.8 μM), and destroyed already formed S. aureus biofilm at concentrations in the range of 6.3-12.5 μM.