Nanomedicine to fight infectious disease

Rubey, Kathryn M.; Brenner, J.

doi:10.1016/j.addr.2021.113996

Cited by 31 publications

(23 citation statements)

References 110 publications

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“…The introduction of antibiotics last century has left the lay public thinking that bacterial infections are a relatively solved problem, but the clinical reality is that these diverse diseases still cause a huge number of deaths and severe illnesses, even when antibiotics are used ( Pneumonia, no date; File and Marrie, 2010; Xu et al , 2020; Rubey and Brenner, 2021). The reasons for incomplete effectiveness include at least 3 major factors: First, the “host response” to bacteria is often deleterious, epitomized by sepsis-induced organ failure(Pechous, 2017; Lelubre and Vincent, 2018).…”

Section: Introductionmentioning

confidence: 99%

Nanoparticle-induced augmentation of neutrophils’ phagocytosis of bacteria

Rubey

Mukhitov

Nong

et al. 2022

Preprint

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Despite the power of antibiotics, bacterial infections remain a major killer, due to antibiotic resistance and hosts with dysregulated immune systems. We and others have been developing drug-loaded nanoparticles that home to the sites of infection and inflammation via engineered tropism for neutrophils, the first-responder leukocytes in bacterial infections. Here, we examined how a member of a broad class of neutrophil-tropic nanoparticles affects neutrophil behavior, specifically questioning whether the nanoparticles attenuate an important function, bacterial phagocytosis. We found these nanoparticles actually augment phagocytosis of non-opsonized bacteria, increasing it by ~50%. We showed this augmentation of phagocytosis is likely co-opting an evolved response, as opsonized bacteria also augment phagocytosis of non-opsonized bacteria. Enhancing phagocytosis of non-opsonized bacteria may prove particularly beneficial in two clinical situations: in hypocomplementemic patients (meaning low levels of the main bacterial opsonins, complement proteins, seen in conditions such as neonatal sepsis and liver failure) or for bacteria that are largely resistant to complement opsonization (e.g., Neisseria). Additionally, we observe that; a) prior treatment with bacteria augments neutrophil uptake of neutrophil-tropic nanoparticles; b) neutrophil-tropic nanoparticles colocalize with bacteria inside of neutrophils. The observation that neutrophil-tropic nanoparticles enhance neutrophil phagocytosis and localize with bacteria inside neutrophils suggests that these nanoparticles will serve as useful carriers for drugs to ameliorate bacterial diseases.

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Section: Introductionmentioning

confidence: 99%

Nanoparticle-induced augmentation of neutrophils’ phagocytosis of bacteria

Rubey

Mukhitov

Nong

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…The introduction of antibiotics last century has left the lay public thinking that bacterial infections are a relatively solved problem, but the clinical reality is that these diverse diseases still cause a huge number of deaths and severe illnesses, even when antibiotics are used ( File and Marrie, 2010 ; Xu et al, 2020 ; Rubey and Brenner, 2021 ; WHO, 2021 ). The reasons for incomplete effectiveness include at least 3 major factors: First, the “host response” to bacteria is often deleterious, epitomized by sepsis-induced organ failure ( Pechous, 2017 ; Lelubre and Vincent, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

“…To solve this problem, we and others have been developing nanoparticles that can deliver drugs directly to the site of infection ( Rubey and Brenner, 2021 ). This approach may address each of the 3 problems listed above, depending on whether the cargo drug is an antibiotic, whose therapeutic index can be improved by localization, or an immunomodulator.…”

Section: Introductionmentioning

confidence: 99%

Nanoparticle-Induced Augmentation of Neutrophils’ Phagocytosis of Bacteria

et al. 2022

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Despite the power of antibiotics, bacterial infections remain a major killer, due to antibiotic resistance and hosts with dysregulated immune systems. We and others have been developing drug-loaded nanoparticles that home to the sites of infection and inflammation via engineered tropism for neutrophils, the first-responder leukocytes in bacterial infections. Here, we examined how a member of a broad class of neutrophil-tropic nanoparticles affects neutrophil behavior, specifically questioning whether the nanoparticles attenuate an important function, bacterial phagocytosis. We found these nanoparticles actually augment phagocytosis of non-opsonized bacteria, increasing it by ∼50%. We showed this augmentation of phagocytosis is likely co-opting an evolved response, as opsonized bacteria also augment phagocytosis of non-opsonized bacteria. Enhancing phagocytosis of non-opsonized bacteria may prove particularly beneficial in two clinical situations: in hypocomplementemic patients (meaning low levels of the main bacterial opsonins, complement proteins, seen in conditions such as neonatal sepsis and liver failure) or for bacteria that are largely resistant to complement opsonization (e.g., Neisseria). Additionally, we observe that; 1) prior treatment with bacteria augments neutrophil uptake of neutrophil-tropic nanoparticles; 2) neutrophil-tropic nanoparticles colocalize with bacteria inside of neutrophils. The observation that neutrophil-tropic nanoparticles enhance neutrophil phagocytosis and localize with bacteria inside neutrophils suggests that these nanoparticles will serve as useful carriers for drugs to ameliorate bacterial diseases.

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“…However, the emergence of multidrug resistance bacteria has threatened to unravel this approach to human and animal health. The global spread of resistant microbes in all areas of disease treatment has left the antibiotic drug pipeline unable to meet demand since compounds are metabolized by voracious multi-drug resistant organisms [1][2][3]. The situation begs for new strategies to combat microbial pathogens [2,[4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

A Structural Approach to Anti-Virulence: A Discovery Pipeline

et al. 2021

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The anti-virulence strategy is designed to prevent bacterial virulence factors produced by pathogenic bacteria from initiating and sustaining an infection. One family of bacterial virulence factors is the mono-ADP-ribosyltransferase toxins, which are produced by pathogens as tools to compromise the target host cell. These toxins are bacterial enzymes that exploit host cellular NAD+ as the donor substrate to modify an essential macromolecule acceptor target in the host cell. This biochemical reaction modifies the target macromolecule (often protein or DNA) and functions in a binary fashion to turn the target activity on or off by blocking or impairing a critical process or pathway in the host. A structural biology approach to the anti-virulence method to neutralize the cytotoxic effect of these factors requires the search and design of small molecules that bind tightly to the enzyme active site and prevent catalytic function essentially disarming the pathogen. This method requires a high-resolution structure to serve as the model for small molecule inhibitor development, which illuminates the path to drug development. This alternative strategy to antibiotic therapy represents a paradigm shift that may circumvent multi-drug resistance in the offending microbe through anti-virulence therapy. In this report, the rationale for the anti-virulence structural approach will be discussed along with recent efforts to apply this method to treat honey bee diseases using natural products.

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Nanomedicine to fight infectious disease

Cited by 31 publications

References 110 publications

Nanoparticle-induced augmentation of neutrophils’ phagocytosis of bacteria

Nanoparticle-induced augmentation of neutrophils’ phagocytosis of bacteria

Nanoparticle-Induced Augmentation of Neutrophils’ Phagocytosis of Bacteria

A Structural Approach to Anti-Virulence: A Discovery Pipeline

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