Apidaecins: Linear Peptide Antibiotics for the Treatment of Serious Gram‐Negative Infections
D. Knappe, A. Gallinat, L. Garoff, D. Hughes, R. Hoffmann, D. Joseph-McCarthy
ABSTRACT | Background: Apidaecins are linear peptide antibiotics (LPAs) with a novel mechanism of action that are aimed at the treatment of serious, drug‐resistant Gram‐negative infections. Apidaecin 1b (GNNRPVYIPQPRPPHPRL‐OH), isolated from Apis melifera (honey bee), is a linear, proline‐rich antimicrobial peptide. Unlike most other classes of antimicrobial peptides (AMPs), apidaecins selectively enter bacterial cellswithout membrane disruption. As a result, they exhibit no mammalian cytotoxicity or hemolytic activity. Apidaecins exert their antibacterial activity through inhibition of protein translation, by binding to the exit tunnel of existing 70S bacterial ribosome which blocks the dissociation of release factors and by preventing the assembly of additional bacterial ribosome. Methods: MICs were determined under standard CLSI methodology in cation‐adjusted Mueller Hinton Broth. Proteolytic stability was evaluated in plasma, serum, and bronchoalveolar lavage of several mammalian species. Results: MICs across a set of Gram‐negative strains including MDR, efflux‐defective, and colistin‐resistant strains are quite promising; e.g., MICs in 25% diluted medium for Api137 were ≤0.125 to 8 μg/ml vs. Eco (n=8) and ≤0.125 to 0.5 μg/ml vs. Kpn (n=6). In the limited studies undertaken we have seen correlation between MICs in 25% diluted medium and in vivo efficacy. The frequency of resistance at 4x MIC for Api137 vs. Eco was similar to that for colistin. In addition, the effect of serum on the MICs is minimal, there is only a small MIC shift in an SmbA knockout Eco strain, and there is no evidence of cross‐resistance with strains resistant to ribosome‐targeting antibiotics. Finally, the proteolytic stability was higher overall in non‐rodent matrices. Conclusions: Taken together with previously reported encouraging in vivo results (in sepsis, thigh infection, and urinary tract infection (UTI) models), this further in vitro characterization of apidaecins supports their continued development as therapeutics, initially for complicated UTIs with a view toward expansion into complicated intra‐abdominal infections and ventilated‐pneumonias.