scholarly journals A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacy

2010 ◽  
Vol 1 (1) ◽  
Author(s):  
Kevin Pethe ◽  
Patricia C. Sequeira ◽  
Sanjay Agarwalla ◽  
Kyu Rhee ◽  
Kelli Kuhen ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Carbon Source ◽  
Genetic Screen ◽  
Growth Inhibitors ◽  
In Vivo Efficacy ◽  
Chemical Genetic ◽  
Dependent Growth

scholarly journals Intracellular localisation of Mycobacterium tuberculosis affects efficacy of the antibiotic pyrazinamide

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pierre Santucci ◽  
Daniel J. Greenwood ◽  
Antony Fearns ◽  
Kai Chen ◽  
Haibo Jiang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Host Cell ◽  
Combination Chemotherapy ◽  
In Vitro Activity ◽  
In Vivo Efficacy ◽  
Human Macrophages ◽  
Ion Microscopy ◽  
Intracellular Localisation

AbstractTo be effective, chemotherapy against tuberculosis (TB) must kill the intracellular population of the pathogen, Mycobacterium tuberculosis. However, how host cell microenvironments affect antibiotic accumulation and efficacy remains unclear. Here, we use correlative light, electron, and ion microscopy to investigate how various microenvironments within human macrophages affect the activity of pyrazinamide (PZA), a key antibiotic against TB. We show that PZA accumulates heterogeneously among individual bacteria in multiple host cell environments. Crucially, PZA accumulation and efficacy is maximal within acidified phagosomes. Bedaquiline, another antibiotic commonly used in combined TB therapy, enhances PZA accumulation via a host cell-mediated mechanism. Thus, intracellular localisation and specific microenvironments affect PZA accumulation and efficacy. Our results may explain the potent in vivo efficacy of PZA, compared to its modest in vitro activity, and its critical contribution to TB combination chemotherapy.

scholarly journals Evaluation of a 2-Pyridone, KRQ-10018, against Mycobacterium tuberculosis In Vitro and In Vivo

2008 ◽  
Vol 52 (4) ◽  
pp. 1513-1515 ◽  
Author(s):  
Anne J. Lenaerts ◽  
Casey Bitting ◽  
Lisa Woolhiser ◽  
Veronica Gruppo ◽  
Karen S. Marietta ◽  
...  
Keyword(s):  
Body Weight ◽  
Mycobacterium Tuberculosis ◽  
In Vivo Efficacy

ABSTRACT A novel subclass of quinolones, 2-pyridones, showed potent activity against Mycobacterium tuberculosis, with KRQ-10018 being an early lead. KRQ-10018 showed better activity in vitro against M. tuberculosis versus moxifloxacin. In vivo efficacy of KRQ-10018 at 300 mg/kg of body weight was similar to that of isoniazid at 25 mg/kg, but showed less activity than moxifloxacin at 300 mg/kg.

scholarly journals Pentacyclic Nitrofurans with In Vivo Efficacy and Activity against Nonreplicating Mycobacterium tuberculosis

PLoS ONE ◽  
2014 ◽  
Vol 9 (2) ◽  
pp. e87909 ◽  
Author(s):  
Rakesh ◽  
David F. Bruhn ◽  
Michael S. Scherman ◽  
Lisa K. Woolhiser ◽  
Dora B. Madhura ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
In Vivo Efficacy

scholarly journals Furoxan derivatives demonstrated in vivo efficacy by reducing Mycobacterium tuberculosis to undetectable levels in a mouse model of infection

2020 ◽  
Vol 130 ◽  
pp. 110592
Author(s):  
P.C. de Souza ◽  
G.F.S. Fernandes ◽  
L.B. Marino ◽  
C.M. Ribeiro ◽  
P.B. da Silva ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mouse Model ◽  
In Vivo Efficacy ◽  
Mouse Model Of Infection

scholarly journals Chemical-genetic interaction mapping links carbon metabolism and cell wall structure to tuberculosis drug efficacy

2021 ◽  
Author(s):  
Eun-Ik Koh ◽  
Nadine Ruecker ◽  
Megan K. Proulx ◽  
Vijay Soni ◽  
Kenan C. Murphy ◽  
...  
Keyword(s):  
Cell Wall ◽  
Mycobacterium Tuberculosis ◽  
Drug Interactions ◽  
Carbon Metabolism ◽  
Drug Efficacy ◽  
Metabolic State ◽  
Chemical Genetic ◽  
Tuberculosis Therapy

AbstractCurrent chemotherapy against Mycobacterium tuberculosis (Mtb), an important human pathogen, requires a multidrug regimen lasting several months. While efforts have been made to optimize therapy by exploiting drug-drug synergies, testing new drug combinations in relevant host environments remains arduous. In particular, host environments profoundly affect the bacterial metabolic state and drug efficacy, limiting the accuracy of predictions based on in vitro assays alone. In this study, we utilize conditional Mtb knockdown mutants of essential genes as an experimentally-tractable surrogate for drug treatment, and probe the relationship between Mtb carbon metabolism and chemical-genetic interactions (CGI). We examined the anti-tubercular drugs isoniazid, rifampicin and moxifloxacin, and found that CGI are differentially responsive to the metabolic state, defining both environment-independent and – dependent synergies. Specifically, growth on the in vivo-relevant carbon source, cholesterol, reduced rifampicin efficacy by altering mycobacterial cell surface lipid composition. We report that a variety of perturbations in cell wall synthesis pathways restore rifampicin efficacy during growth on cholesterol, and that both environment-independent and cholesterol-dependent in vitro CGI could be leveraged to enhance bacterial clearance in the mouse infection model. Our findings present an atlas of novel chemical-genetic-environmental synergies that can be used to optimize drug-drug interactions as well as provide a framework for understanding in vitro correlates of in vivo efficacy.SignificanceEfforts to improve tuberculosis therapy include optimizing multi-drug regimens to take advantage of drug-drug synergies. However, the complex host environment has a profound effect on bacterial metabolic state and drug activity, making predictions of optimal drug combinations difficult. In this study, we leverage a newly developed library of conditional knockdown Mycobacterium tuberculosis mutants in which genetic depletion of essential genes mimics the effect of drug therapy. This tractable system allowed us to assess the effect of growth condition on predicted drug-drug interactions. We found that these interactions can be differentially sensitive to the metabolic state and select in vitro-defined synergies can be leveraged to accelerate bacterial killing during infection. These findings suggest new strategies for optimizing tuberculosis therapy.

scholarly journals An In Vivo Chemical Genetic Screen Identifies Phosphodiesterase 4 as a Pharmacological Target for Hedgehog Signaling Inhibition

Cell Reports ◽  
2015 ◽  
Vol 11 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Charles H. Williams ◽  
Jonathan E. Hempel ◽  
Jijun Hao ◽  
Audrey Y. Frist ◽  
Michelle M. Williams ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Genetic Screen ◽  
Chemical Genetic ◽  
Phosphodiesterase 4 ◽  
Pharmacological Target

Novel N-Linked Aminopiperidine-Based Gyrase Inhibitors with Improved hERG and in Vivo Efficacy against Mycobacterium tuberculosis

2014 ◽  
Vol 57 (11) ◽  
pp. 4889-4905 ◽  
Author(s):  
Shahul Hameed P ◽  
Vikas Patil ◽  
Suresh Solapure ◽  
Umender Sharma ◽  
Prashanti Madhavapeddi ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
In Vivo Efficacy ◽  
Gyrase Inhibitors

scholarly journals Moxifloxacin, Ofloxacin, Sparfloxacin, and Ciprofloxacin against Mycobacterium tuberculosis: Evaluation of In Vitro and Pharmacodynamic Indices That Best Predict In Vivo Efficacy

2006 ◽  
Vol 51 (2) ◽  
pp. 576-582 ◽  
Author(s):  
Radha K. Shandil ◽  
Ramesh Jayaram ◽  
Parvinder Kaur ◽  
Sheshagiri Gaonkar ◽  
B. L. Suresh ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Rank Order ◽  
Dose Fractionation ◽  
In Vitro Assays ◽  
Infection Model ◽  
Unbound Fraction ◽  
In Vivo Efficacy ◽  
Time Kill

ABSTRACT Members of the fluoroquinolone class are being actively evaluated for inclusion in tuberculosis chemotherapy regimens, and we sought to determine the best in vitro and pharmacodynamic predictors of in vivo efficacy in mice. MICs for Mycobacterium tuberculosis H37Rv were 0.1 mg/liter (sparfloxacin [SPX]) and 0.5 mg/liter (moxifloxacin [MXF], ciprofloxacin [CIP], and ofloxacin [OFX]). The unbound fraction in the presence of murine serum was concentration dependent for MXF, OFX, SPX, and CIP. In vitro time-kill studies revealed a time-dependent effect, with the CFU reduction on day 7 similar for all four drugs. However, with a J774A.1 murine macrophage tuberculosis infection model, CIP was ineffective at up to 32× MIC. In addition, MXF, OFX, and SPX exhibited less activity than had been seen in the in vitro time-kill study. After demonstrating that the area under the concentration-time curve (AUC) and maximum concentration of drug in plasma were proportional to the dose in vivo, dose fractionation studies with total oral doses of 37.5 to 19,200 mg/kg of body weight (MXF), 225 to 115,200 mg/kg (OFX), 30 to 50,000 mg/kg (SPX), and 38 to 100,000 mg/kg (CIP) were performed with a murine aerosol infection model. MXF was the most efficacious agent (3.0 ± 0.2 log10 CFU/lung reduction), followed by SPX (1.4 ± 0.1) and OFX (1.5 ± 0.1). CIP showed no effect. The ratio of the AUC to the MIC was the pharmacodynamic parameter that best described the in vivo efficacy. In summary, a lack of intracellular killing predicted the lack of in vivo activity of CIP. The in vivo rank order for maximal efficacy of the three active fluoroquinolones was not clearly predicted by the in vitro assays, however.

scholarly journals Selective Small Molecule Targeting β-Catenin Function Discovered by In Vivo Chemical Genetic Screen

Cell Reports ◽  
2013 ◽  
Vol 4 (5) ◽  
pp. 898-904 ◽  
Author(s):  
Jijun Hao ◽  
Ada Ao ◽  
Li Zhou ◽  
Clare K. Murphy ◽  
Audrey Y. Frist ◽  
...  
Keyword(s):  
Small Molecule ◽  
Genetic Screen ◽  
Chemical Genetic
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