Objective: About half of conventional antibiotics target the bacterial translation apparatus, and many of them play an important role in modern medicine. New-generation translation inhibitors must demonstrate high efficacy against clinically significant antibiotic-resistant bacterial pathogens. It is also imperative that they possess mechanisms of action that differ from those of known antibiotics, thereby reducing the likelihood of cross-resistance. One class of compounds of particular interest is animal-derived proline-rich antimicrobial peptides (PrAMPs). Methods: In this study, we screened 12 natural homologs of previously described cathelicidin Bac7 from Bos taurus, which were discovered through bioinformatic analysis of the genomes of Cetartiodactyla mammals, for their antibacterial activity and ability to inhibit translation. Results and Discussion: A structure-activity relationship analysis enabled the identification of two new homologs that exhibited pronounced activity against bacteria lacking key PrAMP transporter proteins. The high therapeutic potential of the new peptides was demonstrated in an animal model of bacterial septicemia. Conclusions: It has been demonstrated that the analysis of naturally-occurring combinatorial PrAMP libraries is a powerful approach for the search for new valuable antibacterial agents and provides a rich information resource for the development of new antibiotics by modifying the structures of well-known AMPs with a characterized mechanism of action.
Panteleev et al. (Wed,) studied this question.