Bacteriophage and Bacterial Susceptibility, Resistance, and Tolerance to Antibiotics

Chen, Qingquan; Dharmaraj, Tejas; Cai, Pamela C.; Burgener, Elizabeth B.; Haddock, Naomi L.; Spakowitz, Andy J.; Bollyky, Paul L.

doi:10.3390/pharmaceutics14071425

Cited by 44 publications

(21 citation statements)

References 188 publications

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“…26 However, after phage exposure, increased antibiotic susceptibility did occur in our patient, as previously reported in other cases, allowing combination therapy with phages and antibiotics to potentially be more effective than treatment with either alone. [27][28][29][30] Fortunately, no host neutralizing antibody response was detected to either Axy10 or JWX treatment phages in our patient, allowing for their potential use for retreatment if needed, assuming subsequent Achromobacter isolates remain susceptible to these phages.…”

Section: Discussionmentioning

confidence: 74%

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Bacteriophage Therapy of Multidrug-resistant Achromobacter in an 11-Year-old Boy With Cystic Fibrosis Assessed by Metagenome Analysis

Bradley,

Hajama,

Akong

et al. 2023

Pediatric Infectious Disease Journal

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Background: Cystic fibrosis (CF) is a genetic disease associated with lung disease characterized by chronic pulmonary infection, increasingly caused by multiple drug-resistant pathogens after repeated antibiotic exposure, limiting antibiotic treatment options. Bacteriophages can provide a pathogen-specific bactericidal treatment used with antibiotics to improve microbiologic and clinical outcomes in CF. Methods: Achromobacter species isolates from sputum of a chronically infected person with CF, were assessed for susceptibility to bacteriophages: 2 highly active, purified bacteriophages were administered intravenously every 8 hours, in conjunction with a 14-day piperacillin/tazobactam course for CF exacerbation. Sputum and blood were collected for metagenome analysis during treatment, with sputum analysis at 1-month follow-up. Assessments of clinical status, pulmonary status and laboratory evaluation for safety were conducted. Results: Bacteriophage administration was well-tolerated, with no associated clinical or laboratory adverse events. Metagenome analysis documented an 86% decrease in the relative proportion of Achromobacter DNA sequence reads in sputum and a 92% decrease in blood, compared with other bacterial DNA reads, comparing pretreatment and posttreatment samples. Bacteriophage DNA reads were detected in sputum after intravenous administration during treatment, and at 1-month follow-up. Reversal of antibiotic resistance to multiple antibiotics occurred in some isolates during treatment. Stabilization of lung function was documented at 1-month follow-up. Conclusions: Bacteriophage/antibiotic treatment decreased the host pulmonary bacterial burden for Achromobacter assessed by metagenome analysis of sputum and blood, with ongoing bacteriophage replication documented in sputum at 1-month follow-up. Prospective controlled studies are needed to define the dose, route of administration and duration of bacteriophage therapy for both acute and chronic infection in CF.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Bacteriophage Therapy of Multidrug-resistant Achromobacter in an 11-Year-old Boy With Cystic Fibrosis Assessed by Metagenome Analysis

Bradley,

Hajama,

Akong

et al. 2023

Pediatric Infectious Disease Journal

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“…Antimicrobial resistance is a versatile phenotype, contributed by several genetic mechanisms, including two major sets of mechanisms: acquisition of resistance genes, often horizontally, or mutation in conserved genes. So, we suggest that it is possible that plasmid- or integron-acquired resistance has endowed these bacterial strains with phage resistance as well, but this hypothesis remains to be tested ( Ojala et al., 2013 ; Chen et al., 2022 ).…”

Section: Discussionmentioning

confidence: 97%

Characterization and comprehensive genome analysis of novel bacteriophage, vB_Kpn_ZCKp20p, with lytic and anti-biofilm potential against clinical multidrug-resistant Klebsiella pneumoniae

Zaki

Fahmy

Aziz

et al. 2023

Front. Cell. Infect. Microbiol.

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IntroductionThe rise of infections by antibiotic-resistant bacterial pathogens is alarming. Among these, Klebsiella pneumoniae is a leading cause of death by hospital-acquired infections, and its multidrug-resistant strains are flagged as a global threat to human health, which necessitates finding novel antibiotics or alternative therapies. One promising therapeutic alternative is the use of virulent bacteriophages, which specifically target bacteria and coevolve with them to overcome potential resistance. Here, we aimed to discover specific bacteriophages with therapeutic potential against multiresistant K. pneumoniae clinical isolates.Methods and ResultsOut of six bacteriophages that we isolated from urban and medical sewage, phage vB_Kpn_ZCKp20p had the broadest host range and was thus characterized in detail. Transmission electron microscopy suggests vB_Kpn_ZCKp20p to be a tailed phage of the siphoviral morphotype. In vitro evaluation indicated a high lytic efficiency (30 min latent period and burst size of ∼100 PFU/cell), and extended stability at temperatures up to 70°C and a wide range of (2-12) pH. Additionally, phage vB_Kpn_ZCKp20p possesses antibiofilm activity that was evaluated by the crystal violet assay and was not cytotoxic to human skin fibroblasts. The whole genome was sequenced and annotated, uncovering one tRNA gene and 33 genes encoding proteins with assigned functions out of 85 predicted genes. Furthermore, comparative genomics and phylogenetic analysis suggest that vB_Kpn_ZCKp20p most likely represents a new species, but belongs to the same genus as Klebsiella phages ZCKP8 and 6691. Comprehensive genomic and bioinformatics analyses substantiate the safety of the phage and its strictly lytic lifestyle.ConclusionPhage vB_Kpn_ZCKp20p is a novel phage with potential to be used against biofilm-forming K. pneumoniae and could be a promising source for antibacterial and antibiofilm products, which will be individually studied experimentally in future studies.

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“…Another two features returned hits for phage-related proteins. Phages are known to play a role in the horizontal transfer of genes, such as antimicrobial resistance genes [45]. One feature resulted in a hit for an LPXTG-domain-containing protein, which is a part of cell wall anchors but has no known link to disinfectant tolerance thus far.…”

Section: Discussionmentioning

confidence: 99%

Quantitative prediction of disinfectant tolerance inListeria monocytogenesusing whole genome sequencing and machine learning

Gmeiner,

Ivanova,

Kamau Njage

et al. 2023

Preprint

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Listeria monocytogenesis a potentially severe disease-causing bacteria mainly transmitted through food. This pathogen is of great concern for public health and the food industry in particular. Many countries have implemented thorough regulations, and some have even set ‘zero-tolerance’ thresholds for particular food products to minimise the risk ofL. monocytogenesoutbreaks. This emphasises that proper sanitation of food processing plants is of utmost importance. Consequently in recent years, there has been an increased interest inL. monocytogenestolerance to disinfectants used in the food industry. Even though many studies are focusing on laboratory quantification ofL. monocytogenestolerance, the possibility of predictive models remains poorly studied.Within this study, we explore the prediction of tolerance and minimum inhibitory concentrations (MIC) using whole genome sequencing (WGS) and machine learning (ML). We used WGS data and MIC values to quaternary ammonium compound (QAC) disinfectants from 1649L. monocytogenesisolates to train different ML predictors.Our study shows promising results for predicting tolerance to QAC disinfectants using WGS and machine learning. We were able to train high-performing ML classifiers to predict tolerance with balanced accuracy scores up to 0.97±0.02. For the prediction of MIC values, we were able to train ML regressors with mean squared error as low as 0.07±0.02. We also identified several new genes related to cell wall anchor domains, plasmids, and phages, putatively associated with disinfectant tolerance inL. monocytogenes.The findings of this study are a first step towards prediction ofL. monocytogenestolerance to QAC disinfectants used in the food industry. In the future, predictive models might be used to monitor disinfectant tolerance in food production and might support the conceptualisation of more nuanced sanitation programs.AUTHOR SUMMARYMicrobial contamination challenges food safety by potentially transmitting harmful microbes such as bacteria to consumers.Listeria monocytogenesis an example of such a bacteria, which is primarily transmitted through food and can cause severe diseases in at-risk groups. Fortunately, strict food safety regulations and stringent cleaning protocols are in place to prevent the transmission ofListeria monocytogenes. However, in recent years, there has been an increase in tolerance towards disinfectants used in the food industry, which can reduce their effectiveness. In this study, we used genome sequencing and phenotypic data to train machine learning models that can accurately predict whether individualListeria monocytogenesisolates are tolerant to selected disinfectants. We were able to train models that are not only able to distinguish sensitive/tolerant isolates but also can predict different degrees of tolerance to disinfectants. Further, we were able to report a set of genes that were important for the machine learning prediction and could give information about possible tolerance mechanisms. In the future, similar predictive models might be used to guide cleaning and disinfection protocols to facilitate maximum effectiveness.

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Bacteriophage and Bacterial Susceptibility, Resistance, and Tolerance to Antibiotics

Cited by 44 publications

References 188 publications

Bacteriophage Therapy of Multidrug-resistant Achromobacter in an 11-Year-old Boy With Cystic Fibrosis Assessed by Metagenome Analysis

Bacteriophage Therapy of Multidrug-resistant Achromobacter in an 11-Year-old Boy With Cystic Fibrosis Assessed by Metagenome Analysis

Characterization and comprehensive genome analysis of novel bacteriophage, vB_Kpn_ZCKp20p, with lytic and anti-biofilm potential against clinical multidrug-resistant Klebsiella pneumoniae

Quantitative prediction of disinfectant tolerance inListeria monocytogenesusing whole genome sequencing and machine learning

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