Bactericidal Synergism between Phage YC#06 and Antibiotics: a Combination Strategy to Target Multidrug-Resistant Acinetobacter baumannii
            <i>In Vitro</i>
            and
            <i>In Vivo</i>

Luo, Jun; Xie, Linlin; Liu, Min; Li, Qianyuan; Wang, Peng; Luo, Chao

doi:10.1128/spectrum.00096-22

Cited by 18 publications

(19 citation statements)

References 24 publications

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“…their highest identical prophage 95.67% (ON391949.1) Acinetobacter phage YC#06 which is discussed by Luo et al, 2022 they isolated and characterized and used this virulent phage against multidrug-resistant Acinetobacter baumannii strains, moreover the also made antibiotic mixtures with that phage to enhance the effects of phage therapy. [44] After performing BLASTn analysis we found that our selected prophage Acinetobacter baumannii 2759376-2809756 was similar with Podoviral Bacteriophage YMC/09/02/B1251 ABA BP (NC_01954.1) by 96.06% identity. This similar bacteriophage belongs to the family Podoviridae and has a doublestranded circular DNA genome with a length of 45,364 bp and a 39.05% GC content.…”

Section: Discussionmentioning

confidence: 89%

Development of computationally-guided workflow for designing therapeutic phage cocktail: targeting multidrug-resistant (MDR) bacteria

Nawaz

Husnain

Ali

et al. 2023

Preprint

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Background: Antibiotic misuse and overuse have contributed to the emergence of multi-drug resistant bacteria (MDR), a serious public health problem across the globe. Phage cocktails, which combine several phages to destroy various bacterial strains, offer a more thorough and efficient method of battling MDR illnesses. This might revolutionize the looming threat of reemergence of untreatable bacterial diseases. To provide a focused strategy to tackle the rising incidence of MDR bacterial infections, a phage cocktail against Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa was intended to be made computationally. Predicting a group of prophages which can successfully lyse and disrupt these three MDR bacterial strains and might help to lessen the severity and occurrence of illnesses caused by these notorious pathogens. Methods: The genomes of selected MDR bacteria were accessed through NCBI GenBank, and prophages targeting them were selected. The prophages were further annotated for ORFs, putative promotors, virulence factors, transcriptional terminators, and tRNAs. Dot plot was created to investigate the similar phages and phylogenetic analysis was performed. Results: A total of 11 prophages were predicted from three MDR bacterial genomes, the investigation identified 472 ORFs and CDS, rRNA, and tRNA regions in 11 prophage genomes were predicted. The presence of 3 tRNAs encoded by the predicted prophages suggests a possible reliance on the host translation machinery for protein synthesis. The presence of transcription terminators and promotors were detected to understand the transcriptional and translational regulation of prophage genes. The comparative genomic and phylogenetic analyses of predicted prophages provided important insights into diversity and relatedness of the phages. The final selected five prophages included Acinetobacter baumannii prophage (2759376-2809756), Acinetobacter baumannii prophage (3311844-3364667), Klebsiella pneumoniae (1288317-1338719), Klebsiella pneumoniae prophage (1778306-1808606), and Klebsiella pneumoniae prophage (2280703-2325555). Conclusion: In conclusion, our work provides an example of developing a phage cocktail to combat multidrug resistant Acinetobacter baumannii and Klebsiella pneumoniae. Sequence similarity analyses revealed that the cocktail is capable of targeting Enterobacter hormaechei and other carbapenemase-producing K. pneumoniae strains also. The phage cocktail indicates the possibility of being employed as a therapeutic agent for reducing harmful bacterial infections, where conventional antibiotic therapeutics fail.

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Section: Discussionmentioning

confidence: 89%

Development of computationally-guided workflow for designing therapeutic phage cocktail: targeting multidrug-resistant (MDR) bacteria

Nawaz

Husnain

Ali

et al. 2023

Preprint

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“…Controlling the abundance of capsule is also tightly connected to modulation of virulence, and we show here that this control has the additional effect of modulating phage susceptibility, with implications for developing phage-drug synergies [62–64] and for understanding variable capsule production in the pathogen. A. baumannii regulates capsule production through multiple mechanisms, including the BfmRS stress response and stochastic phenotypic switching systems, and the regulatory states associated with higher capsule production show increased virulence [35–38].…”

Section: Discussionmentioning

confidence: 92%

Genome-wide phage susceptibility analysis inAcinetobacter baumanniireveals capsule modulation strategies that determine phage infectivity

Bai

Raustad

Denoncourt

et al. 2022

Preprint

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Phage have gained renewed interest as an adjunctive treatment for life-threatening infections with the drug-resistant nosocomial pathogen Acinetobacter baumannii. Our understanding of the mechanisms used by A. baumannii to defend against phage remains limited, although this information could lead to improved antimicrobial therapies. To address this problem, we used Tn-seq to identify determinants of phage susceptibility in A. baumannii on a genome-wide scale. These studies focused on the lytic phage Loki, which uses unknown mechanisms to target Acinetobacter. We identified 41 candidate loci that increase susceptibility to Loki when disrupted, and 10 that decrease susceptibility. Combined with spontaneous resistance mapping, our results support the model that Loki uses the bacterial capsule as an essential receptor, and that modulation of capsule provides A. baumannii with key strategies to control vulnerability to phage. The center of this control is transcriptional capsule regulation by the two-component system BfmRS. Mutations hyperactivating BfmRS simultaneously increase capsule levels and Loki infectivity, while the opposite is true with BfmRS-inactivating mutations. We identified novel BfmRS-activating mutations, including knockouts of an RNase T2 homolog (RnaA) and the disulfide isomerase DsbA, that determine the outcome of a phage encounter. We further found that mutation of a glycosyltransferase (Gtr6) known to modify capsule structure and virulence in clinical strains can also confer complete phage resistance. Finally, additional factors including the outer core of lipooligosaccharide act independently of capsule modulation to interfere with Loki infection. This work demonstrates that regulatory and structural modulation of capsule, known to alter A. baumannii virulence, is also a major determinant of susceptibility to phage.

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“…In the same way that cocktails of antiretrovirals are used to prevent the emergence of resistance in HIV treatment, it is intriguing to imagine that cocktails of phages and conventional antibiotics, with careful selection, could have utility against AMR pathogens. This approach may have particular utility against biofilm infections or other hard-to-treat infections [ 182 , 183 , 184 , 185 ].…”

Section: Discussionmentioning

confidence: 99%

Bacteriophage and Bacterial Susceptibility, Resistance, and Tolerance to Antibiotics

et al. 2022

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Bacteriophages, viruses that infect and replicate within bacteria, impact bacterial responses to antibiotics in complex ways. Recent studies using lytic bacteriophages to treat bacterial infections (phage therapy) demonstrate that phages can promote susceptibility to chemical antibiotics and that phage/antibiotic synergy is possible. However, both lytic and lysogenic bacteriophages can contribute to antimicrobial resistance. In particular, some phages mediate the horizontal transfer of antibiotic resistance genes between bacteria via transduction and other mechanisms. In addition, chronic infection filamentous phages can promote antimicrobial tolerance, the ability of bacteria to persist in the face of antibiotics. In particular, filamentous phages serve as structural elements in bacterial biofilms and prevent the penetration of antibiotics. Over time, these contributions to antibiotic tolerance favor the selection of resistance clones. Here, we review recent insights into bacteriophage contributions to antibiotic susceptibility, resistance, and tolerance. We discuss the mechanisms involved in these effects and address their impact on bacterial fitness.

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Bactericidal Synergism between Phage YC#06 and Antibiotics: a Combination Strategy to Target Multidrug-Resistant Acinetobacter baumannii In Vitro and In Vivo

Cited by 18 publications

References 24 publications

Development of computationally-guided workflow for designing therapeutic phage cocktail: targeting multidrug-resistant (MDR) bacteria

Development of computationally-guided workflow for designing therapeutic phage cocktail: targeting multidrug-resistant (MDR) bacteria

Genome-wide phage susceptibility analysis inAcinetobacter baumanniireveals capsule modulation strategies that determine phage infectivity

Bacteriophage and Bacterial Susceptibility, Resistance, and Tolerance to Antibiotics

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