Efficacy of chimeric ectolysin P128 in drug-resistant Staphylococcus aureus bacteraemia in mice

J Antimicrob Chemother. 2018 Dec 1;73(12):3398-3404. doi: 10.1093/jac/dky365.


Objectives: P128 is a recombinant chimeric ectolysin with potent antistaphylococcal activity. P128 was evaluated as monotherapy and in combination with two standard-of-care (SoC) antibiotics, vancomycin and daptomycin, in mouse models of Staphylococcus aureus bacteraemia.

Methods: Healthy BALB/c mice were challenged (intraperitoneally) with 109 cfu of MRSA strain COL or USA300 and treated with a single dose of P128 (0.2-10 mg/kg). Drug synergy was tested using a single dose of P128 (0.2 or 2.5 mg/kg) along with sub-therapeutic dose levels of vancomycin (27.5 or 55 mg/kg) or daptomycin (12.5 mg/kg). Bacterial load was checked in peritoneal fluid and in blood, at different time intervals. Synergy against drug-resistant strains was tested using the P128/vancomycin combination against vancomycin-resistant S. aureus (VRSA).

Results: In MRSA bacteraemia, P128, vancomycin and daptomycin monotherapy resulted in 31%, 46% and 46% survival, respectively. The P128/vancomycin and P128/daptomycin combinations afforded increased survival of 85% and 88%, respectively. P128 showed a rapid bactericidal effect with a reduction of cfu in both the peritoneal fluid and the blood within 1 h. In VRSA bacteraemia, a mouse-equivalent therapeutic dose of vancomycin (110 mg/kg) failed to rescue animals. P128 (1-20 mg/kg) as monotherapy resulted in dose-dependent efficacy. Survival (37%) with 2.5 mg/kg P128 increased to 63% with the P128/vancomycin combination.

Conclusions: P128 exerted a rapid bactericidal effect in vivo and rescued animals from fatal invasive MRSA and VRSA infections. P128/SoC antibiotic combinations exerted a synergistic effect. P128 restored the susceptibility of VRSA to vancomycin. P128 is a novel, potent therapeutic agent for antibiotic-resistant, systemic S. aureus infections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Infective Agents / administration & dosage*
  • Ascitic Fluid / microbiology
  • Bacteremia / drug therapy*
  • Bacterial Load
  • Bacteriolysis
  • Blood / microbiology
  • Daptomycin / administration & dosage
  • Disease Models, Animal
  • Drug Synergism
  • Drug Therapy, Combination / methods
  • Female
  • Mice
  • Mice, Inbred BALB C
  • Recombinant Fusion Proteins / administration & dosage*
  • Staphylococcal Infections / drug therapy*
  • Staphylococcus aureus / drug effects
  • Survival Analysis
  • Treatment Outcome
  • Vancomycin / administration & dosage


  • Anti-Infective Agents
  • P128 antistaphylococcal chimeric protein
  • Recombinant Fusion Proteins
  • Vancomycin
  • Daptomycin