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The path of anti-tuberculosis drugs: from blood to lesions to mycobacterial cells

Abstract

For the successful treatment of pulmonary tuberculosis, drugs need to penetrate complex lung lesions and permeate the mycobacterial cell wall in order to reach their intracellular targets. However, most currently used anti-tuberculosis drugs were introduced into clinical use without considering the pharmacokinetic and pharmacodynamic properties that influence drug distribution, and this has contributed to the long duration and limited success of current therapies. In this Progress article, I describe new methods to quantify and image drug distribution in infected lung tissue and in mycobacterial cells, and I explore how this technology could be used to design optimized multidrug regimens.

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Figure 1: The path of anti-TB drugs from the central blood compartment to their molecular target.
Figure 2: Maturation of pulmonary TB lesions.
Figure 3: Drug distribution and imaging in lung tissue and lesions.

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Acknowledgements

The author thanks T. Dick, J. Sarathy and B. Prideaux for many stimulating discussions. V.D. is funded by the Tuberculosis Drug Accelerator program of the Bill and Melinda Gates Foundation and grant R01AI106398-01 from the US National Institutes of Health-National Institute of Allergy and Infectious Diseases (NIH-NIAID).

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Correspondence to Véronique Dartois.

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Glossary

Equilibration half-life

A measure of the time that is required to reach a steady-state drug concentration at the site of drug action, assuming that the concentration remains constant in plasma.

Foamy macrophages

Lipid-loaded macrophages that are found in the inner layers of pulmonary granulomas.

Free drug fraction

The percentage of drug molecules that are not bound to proteins such as albumin, globulins, glycoproteins and lipoproteins; typically calculated in the plasma. It is generally accepted that only this fraction is capable of passively diffusing between body compartments and it is therefore the drug fraction that can exert activity at the site of infection.

HPLC coupled to tandem mass spectrometry

(LC–MS/MS). An analytical method that combines high performance chromatographic separation of analytes with mass-based quantification of molecular ions. Tandem mass spectrometry (MS/MS) enables the quantitation of small-molecule drugs in the complex biological matrices that are typical of biological fluids and tissues.

Intrabacterial pharmacokinetics

The change in drug concentrations over time in individual bacterial cells grown in vitro, in which intracellular drug concentrations change as a result of passive or active uptake, pathogen-mediated metabolism and efflux of the drug.

Liposomes

Artificially prepared vesicles that are composed of a lipid bilayer and are used as vehicles for the administration and slow release of nutrients and pharmaceutical drugs. Liposomes can include surface ligands that enable targeting of specific tissues and cell types.

MALDI mass spectrometry imaging

(MALDI–MSI). A label-free semiquantitative imaging technology that generates two-dimensional ion maps of molecules and their metabolites in biological tissue sections using mass-based detection. MSI preserves the spatial profile and tissue architecture, which enables the high-resolution localization of drugs, lipids and peptides of interest, relative to the underlying tissue structure.

Phagolysosome

A cytoplasmic body that is formed from the fusion of a phagosome (which is a vesicle formed around a particle by phagocytosis) with a lysosome (which contains hydrolytic enzymes).

Pharmacodynamics

The effects that a drug has on an organism (that is, 'how the drug affects the body') or on bacterial cultures in vitro. In the case of antibiotics, this is often determined in animal models of disease and is typically quantified as the difference in bacterial load (or colony forming units (CFU)) over time in selected tissues.

Pharmacokinetics

The change in drug concentrations over time in blood or tissues, which is determined by absorption through the gastrointestinal tract, distribution from one compartment to another, metabolism and elimination from the body. Pharmacokinetics is frequently referred to as 'how the body handles the drug'.

PK–PD parameters

(Pharmacokinetic–pharmacodynamic parameters). The ratios between certain drug-exposure variables (such as peak plasma concentration (Cmax) or area under the concentration–time curve (AUC)) at a given dose and the antibacterial activity (minimum inhibitory concentration) of the drug in vitro. These ratios provide an estimate of in vivo drug exposure relative to in vitro potency, and rules-of-thumb have been established for all of the major antibiotic classes (for example, the efficacy of aminoglycosides is mostly driven by Cmax/MIC). By correlating these parameters with the observed efficacy of the drug in animal models at the corresponding dose, it is possible to predict the dose and dosing frequency that are required to achieve a desired pharmacological effect in patients.

Polyamines

Organic compounds that contain two or more primary amino groups, which are found at reasonably high concentrations in both prokaryotic and eukaryotic cells.

Positron emission tomography

(PET). A nuclear medical and preclinical whole-body imaging modality that produces a three-dimensional image of functional processes or drugs in the body.

Prodrugs

Drugs that are delivered as inactive precursors and that require enzymatic conversion to one or more active derivatives either by the host or by the pathogen. A number of anti-tuberculosis agents are prodrugs, such as isoniazid, pyrazinamide, the thioamides and nitroimidazoles.

SOS response

A global response to DNA damage in bacteria.

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Dartois, V. The path of anti-tuberculosis drugs: from blood to lesions to mycobacterial cells. Nat Rev Microbiol 12, 159–167 (2014). https://doi.org/10.1038/nrmicro3200

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