Phage therapy as an alternative or complementary strategy to prevent and control biofilm-related infections

Pires, Diana Priscila Penso; Melo, Luís D. R.; Boas, Diana Patrícia Andrade Vilas; Sillankorva, Sanna; Azeredo, Joana

doi:10.1016/j.mib.2017.09.004

Cited by 205 publications

(147 citation statements)

References 72 publications

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“…Similarly, recent biofilm PAS studies noted that sequentially treating cells with phage and ciprofloxacin (noted synergism) instead of a simultaneous application (noted antagonism), may have allowed phage replication to occur first before ciprofloxacin's interruption (23,38). These results raise the possibility that the type of interactions in each phage-antibiotic combination is heavily dictated by the primary target of the antibiotic and the cellular processes required for phage replication (34,39,40). Lastly, since protein synthesis inhibitors most likely would interfere with phage production, the dominant synergistic effects seen in kanamycin was unexpected.…”

Section: The Class Of Antibiotic Determines the Type Of Interaction Wmentioning

confidence: 96%

Phage-Antibiotic Synergy is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

Liu

Green

Min

et al. 2020

Preprint

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The continued rise in antibiotic resistance is precipitating a medical crisis. Bacteriophage (phage) has been hailed as one possible therapeutic option to augment the efficacy of antibiotics.However, only a handful of studies have addressed the synergistic relationship between phage and antibiotics. Here, we report a comprehensive analysis of phage-antibiotic interaction that evaluates synergism, additivism, and antagonism for all classes of antibiotics across clinically achievable stoichiometries. We combined an optically-based real-time microtiter plate readout with a matrix-like heatmap of treatment potencies to measure phage and antibiotic synergy (PAS), a process we term synography. Phage-antibiotic synography was performed against a pandemic drug-resistant clonal group of E. coli (ExPEC) with antibiotic levels blanketing the minimum inhibitor concentration (MIC) across seven orders of viral titers. Our results suggest that, under certain conditions, phages provide an adjuvating effect by lowering the MIC for drugresistant strains. Furthermore, synergistic and antagonistic interactions are highly dependent on the mechanism of bacterial inhibition by the class of antibiotic paired to the phage, and when synergism is observed, it suppresses the emergence of resistant cells. Host conditions that simulate the infection environment, including serum and urine, suppress PAS in a bacterial growth-dependent manner. Lastly, phage burst size seems to be a significant driver of synergism.Collectively, this data suggests lytic phages can resuscitate an ineffective antibiotic for previously resistant bacteria, while also synergize with antibiotics in a class-dependent manner, processes that may be dampened by lower bacterial growth rates found in host environments. Significance StatementBacteriophage (phage) therapy is a promising approach to combat the rise of multi-drug resistant bacteria. Currently, the preferred clinical modality is to pair phage with an antibiotic, a practice thought to improve efficacy. However, antagonism between phage and antibiotics has been reported, the choice of phage and antibiotic is not often empirically determined, and the effect of the host factors on the effectiveness is unknown. Here, we interrogate phage-antibiotic interactions across antibiotics with different mechanisms of action. Our results suggest that phage can lower the working MIC for bacterial strains already resistant to the antibiotic, is dependent on the antibiotic class and stoichiometry of the pairing, and is dramatically influenced by the host microenvironment.

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Section: The Class Of Antibiotic Determines the Type Of Interaction Wmentioning

confidence: 96%

Phage-Antibiotic Synergy is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

Liu

Green

Min

et al. 2020

Preprint

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“…Bacteriophage therapy is highly controversial, achieves only a narrow therapeutic spectrum, and comes with fast resistance development (Hughes and Webber, 2017;Pires et al, 2017). However, some promising preclinical results have been achieved using lytic bacteriophages in staphylococcal DRI.…”

Section: Strategies For the Development Of Drugs For The Treatment Ofmentioning

confidence: 99%

Colonization of medical devices by staphylococci

Zheng

Asiamah

et al. 2018

Environmental Microbiology

106

102

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The use of medical devices in modern medicine is constantly increasing. Despite the multiple precautionary strategies that are being employed in hospitals, which include increased hygiene and sterilization measures, bacterial infections on these devices still happen frequently. Staphylococci are among the major causes of medical device infection. This is mostly due to the strong capacity of those bacteria to form device-associated biofilms, which provide resistance to chemical and physical treatments as well as attacks by the host's immune system. Biofilm development is a multistep process with specific factors participating in each step. It is tightly regulated to provide a balance between biofilm expansion and detachment. Detachment from a biofilm on a medical device can lead to severe systemic infection, such as bacteremia and sepsis. While our understanding of staphylococcal biofilm formation has increased significantly and staphylococcal biofilm formation on medical devices is among the best understood biofilm-associated infections, the extensive effort put in preclinical studies with the goal to find novel therapies against staphylococcal device-associated infections has not yet resulted in efficient, applicable therapeutic options for that difficult-to-treat type of disease.

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“…Strategies managing antibiotic-resistant bacteria include antibioticindependent and -dependent methods. The antibioticindependent method includes vaccines, metabolomereprogramming molecules, phage therapy and antibacterial peptides (Peng et al, 2015a;Du et al, 2017;Pires et al, 2017;Wang et al, 2017;Zeng et al, 2017;Zhang et al, 2017;Jiang et al, 2019). Vaccines stimulate the host's active immunity against bacterial pathogens (Guo et al, 2018;Cheng et al, 2018a;Peng et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Metabolome-reprogramming molecules reprogram host's anti-infective metabolome that enhances innate immune responses Cheng et al, 2019;Jiang et al, 2019). Phage therapy and antibacterial peptides attack bacterial cells directly (Pires et al, 2017;Zhang et al, 2017). Whereas the antibiotic-dependent method could be achieved through an antibiotic resistance-reverting molecule or an antibiotic sensitizer to enhance antibiotic killing efficacy (King et al, 2014;Gupta et al, 2014;Peng et al, 2015b;Su et al, 2015;Yao et al, 2016;Su et al, 2018;Yang et al, 2018a;Ye et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Reduced redox‐dependent mechanism and glucose‐mediated reversal in gentamicin‐resistant Vibrio alginolyticus

Zhang

Wang

Jiang

et al. 2019

Environmental Microbiology

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Summary Strategy of managing antibiotic‐resistant Vibrio alginolyticus, a bacterial pathogen that threatens human health and animal farming, is not available due to the lack of knowledge about the underlying mechanism of antibiotic resistance. Here, we showed that gentamicin‐resistant V. alginolyticus (VA‐RGEN) has four mutations on metabolism and one mutation on a two‐component system by whole‐genome and PCR‐based sequencing, indicating the metabolic shift in VA‐RGEN. Thus, metabolic profile was investigated by GC–MS based metabolomics. Glucose was identified as a crucial biomarker, whose abundance was decreased in VA‐RGEN. Further analysis with iPath, and gene expression and enzyme activity of the pyruvate cycle (the P cycle) demonstrated a global depressed metabolic pathway network in VA‐RGEN. Consistently, NADH, sodium‐pumping NADH:ubiquinone oxidoreductase (Na(+)‐NQR) system, membrane potential and intracellular gentamicin were decreased in VA‐RGEN. These findings indicate that the reduced redox state contributes to antibiotic resistance. Interestingly, exogenous glucose potentiated gentamicin to efficiently kill VA‐RGEN through the promotion of the P cycle, NADH, membrane potential and intracellular gentamicin. The potentiation was further confirmed in a zebrafish model. These results indicate that the gentamicin resistance reduces the P cycle and Na(+)‐NQR system and thereby decreases redox state, membrane potential and gentamicin uptake, which can be reversed by exogenous glucose.

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Phage therapy as an alternative or complementary strategy to prevent and control biofilm-related infections

Cited by 205 publications

References 72 publications

Phage-Antibiotic Synergy is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

Phage-Antibiotic Synergy is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

Colonization of medical devices by staphylococci

Reduced redox‐dependent mechanism and glucose‐mediated reversal in gentamicin‐resistant Vibrio alginolyticus

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