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Rational in vitro design of a two-phage cocktail against a contemporary Acinetobacter baumannii strain recovered from a burned patient at CHUV

ABSTRACT: Acinetobacter baumannii is currently a major threat to human health. With the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains, the development of complementary strategies is needed. A promising complimentary and realistic strategy could be phage therapy, which uses bacteriophages (phages), i.e viruses that specifically infect and kill bacterial cells during their life cycle. We designed a two-phage cocktail highly efficient against an extensive drug-resistant (XDR) A. baumannii isolate collected from a patient with burn wound infection at CHUV (termed Ab125). A first in vitro screen of our collection of 34 different phages identified only phage vB_AbaM_3098 as capable of lysing Ab125. However, quick selection of phage-resistant clones (termed Ab139) occurred. Comparative genomics and proteomics between Ab125 and Ab139 revealed several key variations. Very interestingly, we observed that Ab139 became susceptible to six different phages in the collection, otherwise inactive on Ab125. Phage-resistance was also selected when Ab139 was challenged with either of the six phages, with bacterial regrowth observed between 14 h and 16 h. However, combination of vB_AbaM_3098 and vB_AbaM_3014 led to a two-phage cocktail capable of totally inhibiting the growth of Ab125. Treatment with the phage cocktail led to 90% survival after 5 days in the in vivo Galleria Mellonella model of infectious diseases, compared to 0% in the non-treated group. We show that the combination of a phage that only slightly shifted the in vitro bacterial growth curve with an “inactive phage” led to the formulation of a highly bactericidal phage cocktail against Ab125. We then tested the therapeutic potential of the assembled cocktail in synergy with antibiotics and found a synergy with colistin. This work highlights the complexity sometimes involved in the assembly of potent phage cocktail.

INSTRUMENT(S):

ORGANISM(S): Acinetobacter Baumannii (strain Atcc 17978 / Cip 53.77 / Lmg 1025 / Ncdc Kc755 / 5377)

SUBMITTER: Hugues de Villiers de la Noue

LAB HEAD: Grégory Resch

PROVIDER: PXD062593 | Pride | 2025-12-08

REPOSITORIES: Pride

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			Action	DRS
	241021_DeVillier_18355_130min_2ul.raw	Raw
	241021_DeVillier_18357_130min_2ul.raw	Raw
	241021_DeVillier_18358_130min_2ul.raw	Raw
	241021_DeVillier_18359_130min_2ul.raw	Raw
	241021_DeVillier_18360_130min_2ul.raw	Raw

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Rational Design of a Potent Two-Phage Cocktail Against a Contemporary <i>Acinetobacter baumannii</i> Strain Recovered from a Burned Patient at the Lausanne University Hospital.

de Villiers de la Noue Hugues H Golliard Gwenaëlle G Vuattoux Xavier X Resch Grégory G

Viruses 20251029 11

<i>Acinetobacter baumannii</i> 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 strai ...[more]

PMID: 41305464

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Project description:Phages have emerged as prime suspects in the adaptation of pathogens to new hosts and the emergence of new pathogens or epidemic clones. Here we describe the genomic features of “swarms” of three related prophages (Ab105-1ϕ, Ab105-2ϕ and Ab105-3ϕ) present in the ST-2 epidemic clone of Acinetobacter baumannii clinical strain Ab105 GEIH-2010 and not present in genetically related Ab155 GEIH-2000 strain isolated 10 years before. The “Quasicore genome” of Ab105-1ϕ, Ab105-2ϕ and Ab105-3ϕ prophages revealed genes that promote bacterial-host fitness. The results of microarray analysis under stress conditions, SOS response and Quorum Sensing (QS) activation revealed 42% and 21% of genes expressed by Ab105-2ϕ and Ab105-3ϕ prophages (which produce bacterial lysis) in the first case and underexpression of these genes from prophages in the second case. Hence, the QS system plays a major role in the evolution of phages in their natural hosts and environments. Interestingly, in host-virus interactions, RT-PCR showed several mechanisms of overexpression of the SOS response in relation to phage defence mechanisms: i) SAM or AdoMet-MTase (methyltransferases) and MazG protein (pyrophosphohydrolase) associated with phage defence in response to bacterial attack; ii) eukaryotic-like protein kinase (glutamate 5-kinase) associated with prevention of secondary infection by the same or a closely related virus. Overexpression of secretory virulence factors such as oxidoreductase (DsbA-like), anfo-nitrogenase and chromosome segregation proteins were also observed. Moreover, under iron-deficient growth, there was an overexpression by RT-PCR of the a new interesting cluster of genes located following a “Moron” organization in the Ab105-3ϕ prophage being associated with iron uptake systems (Xanthine dehydrogenase gene cluster, Anthranilate operon, ABC transporter and TonB dependent receptor). In conclusion, study of the co-evolution of phages (virus) and bacteria may be essential in the search for means of combatting multi-resistant epidemic clones. Two parental clinical strains of A. baumannii (90% identity, indicated by PFGE, and ST2, indicated by Multilocus Sequence Typing, MLST) isolated in the same Intensive Care Unit (ICU) of a Spanish hospital, in 2000 and 2010, during the “I Multicenter Study GEIH-REIPI-Ab-2000” (Ab155 GEIH-2000) and “II Multicenter Study GEIH-REIPI-Ab-2010” (Ab105 GEIH-2010), respectively. Three replicates from RNA of the AB105 GEIH-2010 strain x 2 conditions (SOS response by Mitomycin C) and (Quorum Sensing activation by AHLs mixture).

Dataset Information

Rational in vitro design of a two-phage cocktail against a contemporary Acinetobacter baumannii strain recovered from a burned patient at CHUV

Dataset's files

Publications

Rational Design of a Potent Two-Phage Cocktail Against a Contemporary <i>Acinetobacter baumannii</i> Strain Recovered from a Burned Patient at the Lausanne University Hospital.

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Dataset Information

Rational in vitro design of a two-phage cocktail against a contemporary Acinetobacter baumannii strain recovered from a burned patient at CHUV

Dataset's files

Publications

Rational Design of a Potent Two-Phage Cocktail Against a Contemporary &lt;i&gt;Acinetobacter baumannii&lt;/i&gt; Strain Recovered from a Burned Patient at the Lausanne University Hospital.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Rational Design of a Potent Two-Phage Cocktail Against a Contemporary <i>Acinetobacter baumannii</i> Strain Recovered from a Burned Patient at the Lausanne University Hospital.