Primary lung dendritic cell cultures to assess efficacy of spectinamide-1599 against intracellular mycobacterium tuberculosis

Karen Santos, Pradeep B. Lukka, Anne Grzegorzewicz, Mary Jackson, Ashit Trivedi, Fernando Pavan, Marlus Chorilli, Miriam Braunstein, Anthony Hickey, Bernd Meibohm, Mercedes Gonzalez-Juarrero

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

There is an urgent need to treat tuberculosis (TB) quickly, effectively and without side effects. Mycobacterium tuberculosis (Mtb), the causative organism of TB, can survive for long periods of time within macrophages and dendritic cells and these intracellular bacilli are difficult to eliminate with current drug regimens. It is well established that Mtb responds differentially to drug treatment depending on its extracellular and intracellular location and replicative state. In this study, we isolated and cultured lung derived dendritic cells to be used as a screening system for drug efficacy against intracellular mycobacteria. Using mono- or combination drug treatments, we studied the action of spectinamide-1599 and pyrazinamide (antibiotics targeting slow-growing bacilli) in killing bacilli located within lung derived dendritic cells. Furthermore, becauseIFN-γ is an essential cytokine produced in response to Mtb infection and present during TB chemotherapy, we also assessed the efficacy of these drugs in the presence and absence ofIFN-γ. Our results demonstrated that monotherapy with either spectinamide-1599 or pyrazinamide can reduce the intracellular bacterial burden by more than 99.9%. Even more impressive is that when TB infected lung derived dendritic cells are treated with spectinamide-1599 and pyrazinamide in combination withIFN-γ a strong synergistic effect was observed, which reduced the intracellular burden below the limit of detection. We concluded that IFN-γ activation of lung derived dendritic cells is essential for synergy between spectinamide-1599 and pyrazinamide.

Original languageEnglish (US)
Article number1895
JournalFrontiers in Microbiology
Volume9
Issue numberJUL
DOIs
StatePublished - Aug 21 2018

Fingerprint

Pyrazinamide
Mycobacterium tuberculosis
Dendritic Cells
Cell Culture Techniques
Tuberculosis
Lung
Bacillus
Pharmaceutical Preparations
Preclinical Drug Evaluations
Mycobacterium Infections
Drug Combinations
Mycobacterium
Limit of Detection
Macrophages
Cytokines
Anti-Bacterial Agents
Drug Therapy
Therapeutics

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Microbiology (medical)

Cite this

Santos, K., Lukka, P. B., Grzegorzewicz, A., Jackson, M., Trivedi, A., Pavan, F., ... Gonzalez-Juarrero, M. (2018). Primary lung dendritic cell cultures to assess efficacy of spectinamide-1599 against intracellular mycobacterium tuberculosis. Frontiers in Microbiology, 9(JUL), [1895]. https://doi.org/10.3389/fmicb.2018.01895

Primary lung dendritic cell cultures to assess efficacy of spectinamide-1599 against intracellular mycobacterium tuberculosis. / Santos, Karen; Lukka, Pradeep B.; Grzegorzewicz, Anne; Jackson, Mary; Trivedi, Ashit; Pavan, Fernando; Chorilli, Marlus; Braunstein, Miriam; Hickey, Anthony; Meibohm, Bernd; Gonzalez-Juarrero, Mercedes.

In: Frontiers in Microbiology, Vol. 9, No. JUL, 1895, 21.08.2018.

Research output: Contribution to journalArticle

Santos, K, Lukka, PB, Grzegorzewicz, A, Jackson, M, Trivedi, A, Pavan, F, Chorilli, M, Braunstein, M, Hickey, A, Meibohm, B & Gonzalez-Juarrero, M 2018, 'Primary lung dendritic cell cultures to assess efficacy of spectinamide-1599 against intracellular mycobacterium tuberculosis', Frontiers in Microbiology, vol. 9, no. JUL, 1895. https://doi.org/10.3389/fmicb.2018.01895
Santos, Karen ; Lukka, Pradeep B. ; Grzegorzewicz, Anne ; Jackson, Mary ; Trivedi, Ashit ; Pavan, Fernando ; Chorilli, Marlus ; Braunstein, Miriam ; Hickey, Anthony ; Meibohm, Bernd ; Gonzalez-Juarrero, Mercedes. / Primary lung dendritic cell cultures to assess efficacy of spectinamide-1599 against intracellular mycobacterium tuberculosis. In: Frontiers in Microbiology. 2018 ; Vol. 9, No. JUL.
@article{7bc082a0400447b3b74e1900ec718f42,
title = "Primary lung dendritic cell cultures to assess efficacy of spectinamide-1599 against intracellular mycobacterium tuberculosis",
abstract = "There is an urgent need to treat tuberculosis (TB) quickly, effectively and without side effects. Mycobacterium tuberculosis (Mtb), the causative organism of TB, can survive for long periods of time within macrophages and dendritic cells and these intracellular bacilli are difficult to eliminate with current drug regimens. It is well established that Mtb responds differentially to drug treatment depending on its extracellular and intracellular location and replicative state. In this study, we isolated and cultured lung derived dendritic cells to be used as a screening system for drug efficacy against intracellular mycobacteria. Using mono- or combination drug treatments, we studied the action of spectinamide-1599 and pyrazinamide (antibiotics targeting slow-growing bacilli) in killing bacilli located within lung derived dendritic cells. Furthermore, becauseIFN-γ is an essential cytokine produced in response to Mtb infection and present during TB chemotherapy, we also assessed the efficacy of these drugs in the presence and absence ofIFN-γ. Our results demonstrated that monotherapy with either spectinamide-1599 or pyrazinamide can reduce the intracellular bacterial burden by more than 99.9{\%}. Even more impressive is that when TB infected lung derived dendritic cells are treated with spectinamide-1599 and pyrazinamide in combination withIFN-γ a strong synergistic effect was observed, which reduced the intracellular burden below the limit of detection. We concluded that IFN-γ activation of lung derived dendritic cells is essential for synergy between spectinamide-1599 and pyrazinamide.",
author = "Karen Santos and Lukka, {Pradeep B.} and Anne Grzegorzewicz and Mary Jackson and Ashit Trivedi and Fernando Pavan and Marlus Chorilli and Miriam Braunstein and Anthony Hickey and Bernd Meibohm and Mercedes Gonzalez-Juarrero",
year = "2018",
month = "8",
day = "21",
doi = "10.3389/fmicb.2018.01895",
language = "English (US)",
volume = "9",
journal = "Frontiers in Microbiology",
issn = "1664-302X",
publisher = "Frontiers Media S. A.",
number = "JUL",

}

TY - JOUR

T1 - Primary lung dendritic cell cultures to assess efficacy of spectinamide-1599 against intracellular mycobacterium tuberculosis

AU - Santos, Karen

AU - Lukka, Pradeep B.

AU - Grzegorzewicz, Anne

AU - Jackson, Mary

AU - Trivedi, Ashit

AU - Pavan, Fernando

AU - Chorilli, Marlus

AU - Braunstein, Miriam

AU - Hickey, Anthony

AU - Meibohm, Bernd

AU - Gonzalez-Juarrero, Mercedes

PY - 2018/8/21

Y1 - 2018/8/21

N2 - There is an urgent need to treat tuberculosis (TB) quickly, effectively and without side effects. Mycobacterium tuberculosis (Mtb), the causative organism of TB, can survive for long periods of time within macrophages and dendritic cells and these intracellular bacilli are difficult to eliminate with current drug regimens. It is well established that Mtb responds differentially to drug treatment depending on its extracellular and intracellular location and replicative state. In this study, we isolated and cultured lung derived dendritic cells to be used as a screening system for drug efficacy against intracellular mycobacteria. Using mono- or combination drug treatments, we studied the action of spectinamide-1599 and pyrazinamide (antibiotics targeting slow-growing bacilli) in killing bacilli located within lung derived dendritic cells. Furthermore, becauseIFN-γ is an essential cytokine produced in response to Mtb infection and present during TB chemotherapy, we also assessed the efficacy of these drugs in the presence and absence ofIFN-γ. Our results demonstrated that monotherapy with either spectinamide-1599 or pyrazinamide can reduce the intracellular bacterial burden by more than 99.9%. Even more impressive is that when TB infected lung derived dendritic cells are treated with spectinamide-1599 and pyrazinamide in combination withIFN-γ a strong synergistic effect was observed, which reduced the intracellular burden below the limit of detection. We concluded that IFN-γ activation of lung derived dendritic cells is essential for synergy between spectinamide-1599 and pyrazinamide.

AB - There is an urgent need to treat tuberculosis (TB) quickly, effectively and without side effects. Mycobacterium tuberculosis (Mtb), the causative organism of TB, can survive for long periods of time within macrophages and dendritic cells and these intracellular bacilli are difficult to eliminate with current drug regimens. It is well established that Mtb responds differentially to drug treatment depending on its extracellular and intracellular location and replicative state. In this study, we isolated and cultured lung derived dendritic cells to be used as a screening system for drug efficacy against intracellular mycobacteria. Using mono- or combination drug treatments, we studied the action of spectinamide-1599 and pyrazinamide (antibiotics targeting slow-growing bacilli) in killing bacilli located within lung derived dendritic cells. Furthermore, becauseIFN-γ is an essential cytokine produced in response to Mtb infection and present during TB chemotherapy, we also assessed the efficacy of these drugs in the presence and absence ofIFN-γ. Our results demonstrated that monotherapy with either spectinamide-1599 or pyrazinamide can reduce the intracellular bacterial burden by more than 99.9%. Even more impressive is that when TB infected lung derived dendritic cells are treated with spectinamide-1599 and pyrazinamide in combination withIFN-γ a strong synergistic effect was observed, which reduced the intracellular burden below the limit of detection. We concluded that IFN-γ activation of lung derived dendritic cells is essential for synergy between spectinamide-1599 and pyrazinamide.

UR - http://www.scopus.com/inward/record.url?scp=85051779416&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85051779416&partnerID=8YFLogxK

U2 - 10.3389/fmicb.2018.01895

DO - 10.3389/fmicb.2018.01895

M3 - Article

VL - 9

JO - Frontiers in Microbiology

JF - Frontiers in Microbiology

SN - 1664-302X

IS - JUL

M1 - 1895

ER -