Phage therapy potentiates second-line antibiotic treatment against pneumonic plague

Vagima, Yaron; Gur, David; Aftalion, Moshe; Moses, Sarit; Levy, Yinon; Makovitzki, Arik; Holtzman, Tzvi; Ziv, Oren; Segula, Yaniv; Fatelevich, Ella; Tidhar, Avital; Zauberman, Ayelet; Rotem, Shahar; Mamroud, Emanuelle; Steinberger-Levy, Ida

doi:10.1101/2022.02.07.479346

Cited by 4 publications

(1 citation statement)

References 37 publications

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“…Antibiotics are generally effective in the treatment of plague, but several antibiotic-resistant strains of Y. pestis have been isolated from patients and rodents in recent years (Cabanel et al, 2018;Sebbane and Lemaitre, 2021). In this context, bacteriophage therapy has been suggested as an alternative, the efficacy of which depends on the administration route (e.g., oral, intramuscular, and aerosol spray) or the frequency of phage application (Anisimov and Amoako, 2006;Sebbane and Lemaitre, 2021;Vagima et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Interplays of mutations in waaA, cmk, and ail contribute to phage resistance in Yersinia pestis

Lin

Zhang

Song

et al. 2023

Front. Cell. Infect. Microbiol.

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Plague caused by Yersinia pestis remains a public health threat worldwide. Because multidrug-resistant Y. pestis strains have been found in both humans and animals, phage therapy has attracted increasing attention as an alternative strategy against plague. However, phage resistance is a potential drawback of phage therapies, and the mechanism of phage resistance in Y. pestis is yet to be investigated. In this study, we obtained a bacteriophage-resistant strain of Y. pestis (S56) by continuously challenging Y. pestis 614F with the bacteriophage Yep-phi. Genome analysis identified three mutations in strain S56: waaA* (9-bp in-frame deletion 249GTCATCGTG257), cmk* (10-bp frameshift deletion 15CCGGTGATAA24), and ail* (1-bp frameshift deletion A538). WaaA (3-deoxy-D-manno-octulosonic acid transferase) is a key enzyme in lipopolysaccharide biosynthesis. The waaA* mutation leads to decreased phage adsorption because of the failure to synthesize the lipopolysaccharide core. The mutation in cmk (encoding cytidine monophosphate kinase) increased phage resistance, independent of phage adsorption, and caused in vitro growth defects in Y. pestis. The mutation in ail inhibited phage adsorption while restoring the growth of the waaA null mutant and accelerating the growth of the cmk null mutant. Our results confirmed that mutations in the WaaA–Cmk–Ail cascade in Y. pestis contribute to resistance against bacteriophage. Our findings help in understanding the interactions between Y. pestis and its phages.

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Section: Introductionmentioning

confidence: 99%

Interplays of mutations in waaA, cmk, and ail contribute to phage resistance in Yersinia pestis

Lin

Zhang

Song

et al. 2023

Front. Cell. Infect. Microbiol.

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A Bacteriophage Cocktail TargetingYersinia pestisProvides Strong Post-Exposure Protection in a Rat Pneumonic Plague Model

Kilgore,

Sha,

Hendrix

et al. 2024

Preprint

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Yersinia pestis, one of the deadliest bacterial pathogens ever known, is responsible for three plague pandemics and several epidemics, with over 200 million deaths during recorded history. Due to high genomic plasticity,Y. pestisis amenable to genetic mutations as well as genetic engineering that can lead to the emergence or intentional development of pan-drug resistant strains. The dissemination of suchY. pestisstrains could be catastrophic, with public health consequences far more daunting than those caused by the recent COVID-19 pandemic. Thus, there is an urgent need to develop novel, safe, and effective treatment approaches for managingY. pestisinfections. This includes infections by antigenically distinct strains for which vaccines, none FDA approved yet, may not be effective, and those that cannot be controlled by approved antibiotics. Lytic bacteriophages provide one such alternative approach. In this study, we examined post-exposure efficacy of a bacteriophage cocktail, YPP-401, to combat pneumonic plague caused byY. pestisCO92. YPP-401 is a four-phage preparation with a 100% lytic activity against a panel of 68 genetically diverseY. pestisstrains. Using a pneumonic plague aerosol challenge model in gender-balanced Brown Norway rats, YPP-401 demonstrated ~88% protection when delivered 18 hours post-exposure for each of two administration routes (i.e., intraperitoneal and intranasal) in a dose-dependent manner. Our studies suggest that YPP-401 could provide an innovative, safe, and effective approach for managingY. pestisinfections, including those caused by naturally occurring or intentionally developed strains that cannot be managed by vaccines in development and antibiotics.

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New Bacteriophages with Podoviridal Morphotypes Active against Yersinia pestis: Characterization and Application Potential

Suladze,

Jaiani,

Darsavelidze

et al. 2023

Viruses

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Phages of highly pathogenic bacteria represent an area of growing interest for bacterial detection and identification and subspecies typing, as well as for phage therapy and environmental decontamination. Eight new phages—YpEc56, YpEc56D, YpEc57, YpEe58, YpEc1, YpEc2, YpEc11, and YpYeO9—expressing lytic activity towards Yersinia pestis revealed a virion morphology consistent with the Podoviridae morphotype. These phages lyse all 68 strains from 2 different sets of Y. pestis isolates, thus limiting their potential application for subtyping of Y. pestis strains but making them rather promising in terms of infection control. Two phages—YpYeO9 and YpEc11—were selected for detailed studies based on their source of isolation and lytic cross activity towards other Enterobacteriaceae. The full genome sequencing demonstrated the virulent nature of new phages. Phage YpYeO9 was identified as a member of the Teseptimavirus genus and YpEc11 was identified as a member of the Helsettvirus genus, thereby representing new species. A bacterial challenge assay in liquid microcosm with a YpYeO9/YpEc11 phage mixture showed elimination of Y. pestis EV76 during 4 h at a P/B ratio of 1000:1. These results, in combination with high lysis stability results of phages in liquid culture, the low frequency of formation of phage resistant mutants, and their viability under different physical–chemical factors indicate their potential for their practical use as an antibacterial mean.

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Phage therapy potentiates second-line antibiotic treatment against pneumonic plague

Cited by 4 publications

References 37 publications

Interplays of mutations in waaA, cmk, and ail contribute to phage resistance in Yersinia pestis

Interplays of mutations in waaA, cmk, and ail contribute to phage resistance in Yersinia pestis

A Bacteriophage Cocktail TargetingYersinia pestisProvides Strong Post-Exposure Protection in a Rat Pneumonic Plague Model

New Bacteriophages with Podoviridal Morphotypes Active against Yersinia pestis: Characterization and Application Potential

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