An Oral Fluorouracil Prodrug, Capecitabine, Mitigates a Gram-Positive Systemic Infection in Mice

McLeod, J.; Harvey, Pamela A.; Detweiler, Corrella S.

doi:10.1128/spectrum.00275-21

Cited by 9 publications

(9 citation statements)

References 73 publications

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“…S. aureus FDA209 (ATCC 6538), S. aureus HG001 (AH2183), S. aureus USA300, and S. epidermidis 1457 (AH2490). S. aureus FDA209 was isolated from a skin lesion, is sensitive to antibiotics, and has historically been used in antimicrobial and quality control testing ( 58–60 ). S. aureus HG001 is a common lab strain derivative of NCTC835, a methicillin-sensitive strain isolated from a septic patient but with a restored rsbU1 gene to increase its biofilm production (61, 62).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Multiple Staphylococcal Growth States by a Small Molecule that Disrupts Membrane Fluidity and Voltage

Dombach,

Christensen,

Allgood

et al. 2024

Preprint

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New molecular approaches to disrupting bacterial infections are needed. The bacterial cell membrane is an essential structure with diverse potential lipid and protein targets for antimicrobials. While rapid lysis of the bacterial cell membrane kills bacteria, lytic compounds are generally toxic to whole animals. In contrast, compounds that subtly damage the bacterial cell membrane could disable a microbe, facilitating pathogen clearance by the immune system with limited compound toxicity. A previously described small molecule, D66, terminates Salmonella enterica serotype Typhimurium (S. Typhimurium) infection of macrophages and reduces tissue colonization in mice. The compound dissipates bacterial inner membrane voltage without rapid cell lysis under broth conditions that permeabilize the outer membrane or disable efflux pumps. In standard media, the cell envelope protects Gram-negative bacteria from D66. We evaluated the activity of D66 in Gram-positive bacteria because their distinct envelope structure, specifically the absence of an outer membrane, could facilitate mechanism of action studies. We observed that D66 inhibited Gram-positive bacterial cell growth, rapidly increased Staphylococcus aureus membrane fluidity, and disrupted membrane voltage while barrier function remained intact. The compound also prevented planktonic staphylococcus from forming biofilms and disturbed three-dimensional structure in one-day-old biofilms. D66 furthermore reduced the survival of staphylococcal persister cells and of intracellular S. aureus. These data indicate that staphylococcal cells in multiple growth states germane to infection are susceptible to changes in lipid packing and membrane conductivity. Thus, agents that subtly damage bacterial cell membranes could have utility in preventing or treating disease.

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Section: Methodsmentioning

confidence: 99%

Inhibition of Multiple Staphylococcal Growth States by a Small Molecule that Disrupts Membrane Fluidity and Voltage

Dombach,

Christensen,

Allgood

et al. 2024

Preprint

Self Cite

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“…S. aureus FDA209 (ATCC 6538), S. aureus HG001 (AH2183), S. aureus USA300, and S. epidermidis 1457 (AH2490) are the bacterial strains used. S. aureus FDA209 was isolated from a skin lesion, is sensitive to antibiotics, and has historically been used in antimicrobial and quality control testing ( 58 – 60 ). S. aureus HG001 is a common lab strain derivative of NCTC835, a methicillin-sensitive strain isolated from a septic patient but with a restored rsbU1 gene to increase its biofilm production ( 61 , 62 ).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of multiple staphylococcal growth states by a small molecule that disrupts membrane fluidity and voltage

Dombach,

Christensen,

Allgood

et al. 2024

mSphere

Self Cite

View full text Add to dashboard Cite

New molecular approaches to disrupting bacterial infections are needed. The bacterial cell membrane is an essential structure with diverse potential lipid and protein targets for antimicrobials. While rapid lysis of the bacterial cell membrane kills bacteria, lytic compounds are generally toxic to whole animals. In contrast, compounds that subtly damage the bacterial cell membrane could disable a microbe, facilitating pathogen clearance by the immune system with limited compound toxicity. A previously described small molecule, D66, terminates Salmonella enterica serotype Typhimurium ( S . Typhimurium) infection of macrophages and reduces tissue colonization in mice. The compound dissipates bacterial inner membrane voltage without rapid cell lysis under broth conditions that permeabilize the outer membrane or disable efflux pumps. In standard media, the cell envelope protects Gram-negative bacteria from D66. We evaluated the activity of D66 in Gram-positive bacteria because their distinct envelope structure, specifically the absence of an outer membrane, could facilitate mechanism of action studies. We observed that D66 inhibited Gram-positive bacterial cell growth, rapidly increased Staphylococcus aureus membrane fluidity, and disrupted membrane voltage while barrier function remained intact. The compound also prevented planktonic staphylococcus from forming biofilms and a disturbed three-dimensional structure in 1-day-old biofilms. D66 furthermore reduced the survival of staphylococcal persister cells and of intracellular S. aureus . These data indicate that staphylococcal cells in multiple growth states germane to infection are susceptible to changes in lipid packing and membrane conductivity. Thus, agents that subtly damage bacterial cell membranes could have utility in preventing or treating disease. IMPORTANCE An underutilized potential antibacterial target is the cell membrane, which supports or associates with approximately half of bacterial proteins and has a phospholipid makeup distinct from mammalian cell membranes. Previously, an experimental small molecule, D66, was shown to subtly damage Gram-negative bacterial cell membranes and to disrupt infection of mammalian cells. Here, we show that D66 increases the fluidity of Gram-positive bacterial cell membranes, dissipates membrane voltage, and inhibits the human pathogen Staphylococcus aureus in several infection-relevant growth states. Thus, compounds that cause membrane damage without lysing cells could be useful for mitigating infections caused by S. aureus .

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“…The widely used antimetabolite 5-FU was used as a model drug. Since 5-FU has been shown to have antibacterial activity by disrupting DNA metabolism in Gram-positive bacteria (46,47), the effect of 5-FU on MTB was first investigated. To ensure that viability of Gram-negative MTB is not compromised by 5-FU, live-dead staining was performed.…”

Section: Complementary Therapeutic Effects Of Mtb-lpmentioning

confidence: 99%

Engineering living immunotherapeutic agents for improved cancer treatment

Gwisai

Günther

Vizovišek

et al. 2023

Preprint

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Bacteria-based biohybrid agents are emerging as a promising strategy for cancer therapy due to their ability to actively target tumors, trigger localized inflammation and induce tumor regression. There has been growing interest in using bacteria that are responsive to external cues, such as magnetic fields, to facilitate the formation of robust colonies in tumor the achieve the threshold for clinical efficacy. Several studied have demonstrated the potential of innately magnetically responsive bacteria, known as magnetotactic bacteria (MTB), as steerable agents, however, their immunostimulatory properties and therapeutic effects are yet to be explored. Here, we characterize key properties of human immune cell responses and the behavior of the MTB strain Magnetospirillum magneticum AMB-1 in physiological environments. This work investigates the ability of MTB to maintain magnetic properties, viability in whole blood, cytokine production by macrophages, and the ability to increase uptake of cancer cell material by dendritic cells. This study also explores the use of MTB-liposome complexes for effective delivery of therapeutic payloads. Overall, this study establishes the potential of MTB as a versatile, combined drug delivery platform for immune-mediated cancer therapy.

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An Oral Fluorouracil Prodrug, Capecitabine, Mitigates a Gram-Positive Systemic Infection in Mice

Cited by 9 publications

References 73 publications

Inhibition of Multiple Staphylococcal Growth States by a Small Molecule that Disrupts Membrane Fluidity and Voltage

Inhibition of Multiple Staphylococcal Growth States by a Small Molecule that Disrupts Membrane Fluidity and Voltage

Inhibition of multiple staphylococcal growth states by a small molecule that disrupts membrane fluidity and voltage

Engineering living immunotherapeutic agents for improved cancer treatment

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