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The peptide Api88 is a novel, 18-residue antimicrobial lead compound with favorable in vitro properties and in vivo efficacy against bacteria in models of lethal sepsis. Radioactive labeling studies showed that the peptide crosses the blood-brain barrier and is clear from the body within 24 h of administration. Api88 rescued mice from a lethal intraperitoneal infection of E. coli strain ATCC 25922 using two different sepsis models. The peptide’s in vivo efficacy was similar to that of the apidaecin analogues Api137 and Onc72, which both exhibited strong bactericidal activity against E. coli and other Gram-negative bacteria.
Gene-encoded antimicrobial peptides kill bacteria with either lytic mechanisms or inhibition of specific bacterial targets. Proline-rich AMPs such as apidaecin 1b, originally identified in honey bees, and two rationally optimized analogues, Api88 and Api137, bind to the 70 kDa heat shock protein DnaK and 60 kDa chaperonin GroEL and interfere with protein folding. They exhibit excellent bactericidal activities and are therefore a promising target for the development of novel antibiotics.
In a recent study, the researchers found that the molecular dynamics simulations of the complex -peptide apidaecin 1b were consistent with the in vivo behavior observed in mouse sepsis model. These results suggest that -peptide apidaecin has a unique mechanism of action that may explain its broad spectrum in vivo antimicrobial activity. The authors further investigated the molecular mechanism of apidaecin’s antimicrobial activity and found that it inhibits protein synthesis in bacteria by targeting the bacterial ribosome. They further confirmed that apidaecin is a potent peptidomimetic by investigating the binding affinity of the molecule for a number of bacterial targets and evaluating its in vivo clearance in mice. They conclude that apidaecin’s in vivo efficacy is due to the inhibition of the bacterial ribosome and cytoplasmic vacuoles. In addition, the molecular mechanism of apidaecin’s toxicity was studied in a murine cancer cell line and its impact on tumorigenesis.
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