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Published on: December 10, 2016
The designer proline-rich antibacterial peptide A3-APO is effective against systemic Escherichia coli infections in
Dora Szabo1, Eszter Ostorhazi, Annegret Binas
1Institute of Medical Microbiology, Semmelweis University, Budapest, Hungary.
Abstract:
Antimicrobial peptides are considered to be viable alternatives to conventional antibiotics. However, they rarely show systemic efficacy in animal models when added at non-toxic doses. The dimer A3-APO was designed to attack both the bacterial membrane and the Enterobacteriaceae-specific domain of the heat shock protein DnaK in order to reduce toxicity whilst maintaining activity. The peptide exhibited a minimal inhibitory concentration (MIC) range of 2-128 mg/L against 28 clinical Escherichia coli, Klebsiella pneumoniae and Salmonella enterica serovar Typhimurium strains, with a median MIC of 30 mg/L. At this concentration, A3-APO was bactericidal to E. coli 5770, a fluoroquinolone-resistant extended-spectrum beta-lactamase-producing strain. The No Observed Adverse Effect Limit (NOAEL) at repeated intraperitoneal peptide administration was 20mg/kg. When administered at this dose three times starting immediately after E. coli Neumann infection, A3-APO cured 100% of mice in a standard bacteraemia model used by the pharmaceutical industry. In a more stringent assay, when treatment started after E. coli 5770 bacteraemia had already been established, three doses of 10mg/kg A3-APO prolonged early survival at a rate similar to that of imipenem and reduced the bacterial counts to base level. When the second assay was repeated in kidney clearance conditions resembling those in humans, 10mg/kg A3-APO was as efficacious as imipenem in the long-term. The increased in vivo efficacy compared with the in vitro bactericidal figures can potentially be explained by the generally observable immunostimulatory properties of antimicrobial peptides. Peptide A3-APO shows promising features as a member in our antibiotic arsenal against multidrug-resistant bacterial pathogens.
Insights
Antimicrobial peptide A3-APO shows promise against multidrug-resistant bacteria. It effectively treated infections in mice at non-toxic doses, demonstrating potential as a new antibiotic alternative.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Antimicrobial peptides (AMPs) offer alternatives to conventional antibiotics but often lack systemic efficacy.
- Toxicity and limited activity hinder AMPs' clinical application.
- Developing novel AMPs with improved safety and efficacy profiles is crucial.
Purpose of the Study:
- To design and evaluate the novel dimeric antimicrobial peptide A3-APO.
- To assess A3-APO's efficacy against multidrug-resistant Gram-negative bacteria in vitro and in vivo.
- To determine the safety and therapeutic potential of A3-APO in preclinical models.
Main Methods:
- A3-APO was designed to target bacterial membranes and the DnaK protein.
- Minimal inhibitory concentrations (MICs) were determined against clinical isolates of E. coli, K. pneumoniae, and S. enterica.
- In vivo efficacy was evaluated in mouse bacteremia models, including early and established infection, and kidney clearance models.
Main Results:
- A3-APO demonstrated potent in vitro activity with a median MIC of 30 mg/L against resistant strains.
- The peptide showed a No Observed Adverse Effect Limit (NOAEL) of 20 mg/kg in mice.
- A3-APO achieved 100% cure rates in an early infection model and prolonged survival in established infection models, comparable to imipenem.
Conclusions:
- A3-APO exhibits significant in vitro and in vivo efficacy against multidrug-resistant Gram-negative pathogens.
- The peptide demonstrates a favorable safety profile and potential for systemic application.
- A3-APO represents a promising candidate for novel antibiotic development against resistant bacterial infections.
