Optimal design of thiostrepton-derived thiopeptide antibiotics and their potential application against oral pathogens

Thiostrepton (TSR), produced by Streptomyces laurentii, is a potent archetypal thiopeptide antibiotic that effectively antagonizes a broad spectrum of Gram-positive bacteria and has been used as a safe antimicrobial agent for animals. Siomycin (SIO) is a naturally produced TSR-type antibiotic that has been reported more potent than TSR. Based on a recent understanding regarding the structure–activity relationship of TSR against prokaryotic pathogens, we here constructed an ideal platform to obtain quinaldic acid (QA)-modified SIO analogs and generated a new SIO derivative, 5′-fluoro-SIO, with an unanticipated improvement in water solubility. To investigate whether oral diseases could be developed as novel indications for TSR-type antibiotics, we tested the minimum inhibitory concentrations (MICs) of these antibiotics against common oral pathogenetic microorganisms. Quantitative bioassays indicated that all of the tested TSR-type antibiotics exhibited potent antibacterial activity against the Gram-positive cariogenic microorganisms involved in the development of dental caries, as well as two major Gram-negative periodontal pathogens. Among the tested antibiotics, 5′-fluoro-SIO and SIO exhibited stronger potency than 5′-fluoro-TSR and TSR. These findings suggest that SIO may be more suitable than TSR as a lead compound to develop improved thiopeptide derivatives for clinical use and that TSR-type antibiotics have considerable potential for the prevention and treatment of dental caries and periodontitis.