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Rational Design of a Potent Two-Phage Cocktail Against a Contemporary Acinetobacter baumannii Strain Recovered from a
Hugues de Villiers de la Noue1, Gwenaëlle Golliard1, Xavier Vuattoux1
1Laboratory of Bacteriophages and Phage Therapy, Center for Research and Innovation in Clinical Pharmaceutical Sciences (CRISP), Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), 1005 Lausanne, Switzerland.
Abstract:
Acinetobacter baumannii is a critical public health threat, particularly with the rise in multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains that limit treatment options. Phage therapy, which uses bacteriophages to target bacteria, offers a promising alternative. We isolated an XDR strain (Ab125) from a burn wound infection and screened 34 phages, identifying vB_AbaM_3098 as the only effective candidate. However, resistance rapidly emerged, producing a derivative strain (Ab139). Interestingly, Ab139, though resistant to vB_AbaM_3098, became susceptible to six previously inactive phages. While various potential determinants were identified through comparative genomics and proteomics, the mechanism causing phage resistance to vB_AbaM_3098 and simultaneous susceptibility to other phages remains to be elucidated. Among the six new candidates, vB_AbaM_3014 was the most promising. While each phage alone allowed bacterial regrowth, combining vB_AbaM_3098 and vB_AbaM_3014 completely suppressed Ab125 growth. In a Galleria mellonella infection model, this cocktail achieved 90% survival after five days compared to 0% in untreated controls. Notably, the cocktail combined one phage with modest activity and another inactive phage against the parental strain; together, they produced strong bactericidal effects. These findings highlight both the complexity of phage cocktail design and their promise as adjunct therapies against drug-resistant A. baumannii.
Insights
Phage therapy shows promise against drug-resistant Acinetobacter baumannii. A combination of two bacteriophages (phages) effectively suppressed bacterial growth and improved survival in a model infection, offering a new therapeutic strategy.
Area of Science:
- Microbiology
- Bacteriology
- Antimicrobial Resistance
Background:
- Acinetobacter baumannii is a significant public health concern due to increasing multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains.
- Phage therapy, utilizing bacteriophages, presents a potential alternative to conventional antibiotics for treating resistant bacterial infections.
Purpose of the Study:
- To investigate the efficacy of bacteriophages as a therapeutic strategy against extensively drug-resistant Acinetobacter baumannii.
- To explore phage resistance development and identify effective phage combinations for treating Acinetobacter baumannii infections.
Main Methods:
- Isolation of an XDR Acinetobacter baumannii strain (Ab125) from a burn wound infection.
- Screening of 34 bacteriophages and identification of effective candidates, including vB_AbaM_3098 and vB_AbaM_3014.
- Comparative genomics and proteomics to analyze phage resistance mechanisms.
- Evaluation of phage cocktail efficacy in a Galleria mellonella infection model.
Main Results:
- A single phage (vB_AbaM_3098) showed initial efficacy, but rapid resistance emerged in the derivative strain (Ab139).
- The resistant strain (Ab139) became susceptible to other previously ineffective phages, indicating complex resistance mechanisms.
- A combination of vB_AbaM_3098 and vB_AbaM_3014 completely inhibited the growth of the parental strain (Ab125).
- The phage cocktail demonstrated significant efficacy in the Galleria mellonella model, achieving 90% survival.
Conclusions:
- Phage therapy, particularly using carefully designed cocktails, holds significant promise for treating extensively drug-resistant Acinetobacter baumannii infections.
- Understanding phage resistance mechanisms is crucial for optimizing phage cocktail design and therapeutic success.
- Combined phage therapy can overcome resistance and provide potent bactericidal effects against challenging bacterial pathogens.
