Depolymerase as a potent adjunct to polymyxin for targeting KL160 pandrug-resistant Acinetobacter baumannii in a murine bacteremia model.
Summary
A KL160-specific phage-derived depolymerase (DPO-HL) synergized with polymyxin B, reducing polymyxin MIC 16-fold and achieving 100% survival in a murine pandrug-resistant A. baumannii bacteremia model while lowering endotoxin levels. DPO-HL was plasma-stable, enhanced plasma bactericidal activity, eradicated mature biofilms, and showed acceptable safety in vitro and in vivo.
Key Findings
- DPO-HL was stable in human plasma and enhanced plasma bactericidal activity.
- Synergy with polymyxin B reduced polymyxin MIC by 16-fold and eradicated mature biofilms.
- Combination therapy (1.45 mg/kg DPO-HL + 0.5 mg/kg polymyxin B) achieved 100% survival and reduced endotoxin; DPO-HL monotherapy rescued 30%.
Clinical Implications
If validated in humans, depolymerase–polymyxin combinations could reduce doses, toxicity, and resistance emergence against A. baumannii sepsis. Capsular typing (e.g., KL160) may guide adjuvant selection.
Why It Matters
This is among the first demonstrations in a mammalian sepsis model that a capsular depolymerase can rescue lethal pandrug-resistant A. baumannii bacteremia via synergy with a last-line antibiotic. It opens a translational path for enzyme–antibiotic combinations against critical AMR pathogens.
Limitations
- Preclinical murine model; human efficacy and immunogenicity are unknown.
- Targeted a single capsular type (KL160), limiting immediate generalizability across A. baumannii strains.
Future Directions
Evaluate immunogenicity, pharmacokinetics, and efficacy across diverse capsular types; design first-in-human safety studies and optimize combination dosing strategies.
Study Information
- Study Type
- Case series
- Research Domain
- Treatment
- Evidence Level
- IV - Preclinical animal experiment analogous to a case series; no human subjects.
- Study Design
- OTHER