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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World Health Organization. Global Tuberculosis Report (WHO, 2012).
Bass, J. B. Jr et al. Treatment of tuberculosis and tuberculosis infection in adults and children. American Thoracic Society and the Centers for Disease Control and Prevention. Am. J. Respir. Crit. Care Med. 149, 1359–1374 (1994).
Bates, J. H. & Nardell, E. Institutional control measures for tuberculosis in the era of multiple drug resistance: ACCP/ATS Consensus Conference. Chest 108, 1690–1710 (1995).
Monedero, I. & Caminero, J. A. MDR-/XDR-TB management: what it was, current standards and what is ahead. Expert Rev. Respir. Med. 3, 133–145 (2009).
Caminero, J. A., Sotgiu, G., Zumla, A. & Migliori, G. B. Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Lancet Infect. Dis. 10, 621–629 (2010).
Golden, M. P. & Vikram, H. R. Extrapulmonary tuberculosis. Am. Family Physician 72, 1761–1768 (2005).
Diacon, A. H. et al. Early bactericidal activity of high-dose rifampin in patients with pulmonary tuberculosis evidenced by positive sputum smears. Antimicrob. Agents Chemother. 51, 2994–2996 (2007).
van Ingen, J. et al. Why do we use 600 mg of rifampicin in tuberculosis treatment? Clin. Infect. Dis. 52, e194–e199 (2011).
Nielsen, E. I. & Friberg, L. E. Pharmacokinetic–pharmacodynamic modeling of antibacterial drugs. Pharmacol. Rev. 65, 1053–1090 (2013).
Egelund, E. F., Barth, A. B. & Peloquin, C. A. Population pharmacokinetics and its role in anti-tuberculosis drug development and optimization of treatment. Curr. Pharm. Des. 17, 2889–2899 (2011).
Kjellsson, M. C. et al. Pharmacokinetic evaluation of the penetration of antituberculosis agents in rabbit pulmonary lesions. Antimicrob. Agents Chemother. 56, 446–457 (2012).
Russell, D. G., Cardona, P. J., Kim, M. J., Allain, S. & Altare, F. Foamy macrophages and the progression of the human tuberculosis granuloma. Nature Immunol. 10, 943–948 (2009).
Davis, J. M. & Ramakrishnan, L. The role of the granuloma in expansion and dissemination of early tuberculous infection. Cell 136, 37–49 (2009).
Silva Miranda, M., Breiman, A., Allain, S., Deknuydt, F. & Altare, F. The tuberculous granuloma: an unsuccessful host defence mechanism providing a safety shelter for the bacteria? Clin. Dev. Immunol. 2012, 139127 (2012).
Leong, F. J., Eum, S. Y., Via, L. E. & Barry, C. E. 3rd. in A Color Atlas of Comparative Pathology of Pulmonary Tuberculosis (eds Leong F. J., Dartois, V., Dick, T) 53–81 (CRC Press, 2011).
Vergne, I. et al. Mechanism of phagolysosome biogenesis block by viable Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 102, 4033–4038 (2005).
Simeone, R. et al. Phagosomal rupture by Mycobacterium tuberculosis results in toxicity and host cell death. PLoS Pathog. 8, e1002507 (2012).
Seiler, P. et al. Cell-wall alterations as an attribute of Mycobacterium tuberculosis in latent infection. J. Infect. Dis. 188, 1326–1331 (2003).
Fenhalls, G. et al. In situ detection of Mycobacterium tuberculosis transcripts in human lung granulomas reveals differential gene expression in necrotic lesions. Infect. Immun. 70, 6330–6338 (2002).
Ryan, G. J. et al. Multiple M. tuberculosis phenotypes in mouse and guinea pig lung tissue revealed by a dual-staining approach. PLoS ONE 5, e11108 (2010).
Driver, E. R. et al. Evaluation of a mouse model of necrotic granuloma formation using C3HeB/FeJ mice for testing of drugs against Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 56, 3181–3195 (2012).
Hoff, D. R. et al. Location of intra- and extracellular M. tuberculosis populations in lungs of mice and guinea pigs during disease progression and after drug treatment. PLoS ONE 6, e17550 (2010).
Eum, S. Y. et al. Neutrophils are the predominant infected phagocytic cells in the airways of patients with active pulmonary TB. Chest 137, 122–128 (2010).
Rubin, E. J. The granuloma in tuberculosis — friend or foe? N. Engl. J. Med. 360, 2471–2473 (2009).
Dartois, V. & Barry, C. E. 3rd. A medicinal chemists' guide to the unique difficulties of lead optimization for tuberculosis. Bioorg. Med. Chem. Lett. 23, 4741–4750 (2013).
Dartois, V. & Barry, C. E. Clinical pharmacology and lesion penetrating properties of second- and third-line antituberculous agents used in the management of multidrug-resistant (MDR) and extensively-drug resistant (XDR) tuberculosis. Curr. Clin. Pharmacol. 5, 96–114 (2010).
Minchinton, A. I. & Tannock, I. F. Drug penetration in solid tumours. Nature Rev. Cancer 6, 583–592 (2006).
Kyle, A. H., Huxham, L. A., Yeoman, D. M. & Minchinton, A. I. Limited tissue penetration of taxanes: a mechanism for resistance in solid tumors. Clin. Cancer Res. 13, 2804–2810 (2007).
Kaplan, G. et al. Mycobacterium tuberculosis growth at the cavity surface: a microenvironment with failed immunity. Infect. Immun. 71, 7099–7108 (2003).
Barclay, W. R., Ebert, R. H., Le Roy, G. V., Manthei, R. W. & Roth, L. J. Distribution and excretion of radioactive isoniazid in tuberculous patients. J. Am. Med. Assoc. 151, 1384–1388 (1953).
Kislitsyna, N. A. & Kotova, N. I. Rifampicin and isoniazid concentration in the blood and resected lungs in tuberculosis with combined use of the preparations. Probl Tuberk 8, 63–65 (in Russian) (1980).
Canetti, G., Parrot, R., Porven, G. & Le Lirzin, M. Rifomycin levels in the lung and tuberculous lesions in man. Acta Tuberc Pneumol Belg. 60, 315–322 (in French) (1969).
Kiss, I. J., Farago, E., Juhaz, I., Bacsa, S. & Fabian, E. Investigation on the serum and lung tissue level of rifampicin in man. Int. J. Clin. Pharmacol. Biopharm. 13, 42–47 (1976).
Kislitsyna, N. A. Comparative evaluation of rifampicin and isoniazid penetration into the pathological foci of the lungs in tuberculosis patients. Probl Tuberk 4, 55–57 (in Russian) (1985).
Dannenberg, A. M. Jr. in Pathogenesis of Human Pulmonary Tuberculosis 22–33 (ASM Press, 2006).
Kaplan, G. & Tsenova, L. in A Color Atlas of Comparative Pathology of Pulmonary Tuberculosis: (eds Leong, F. J., Dartois, V. & Dick, T.) 107–128 (CRC Press, 2011).
Subbian, S. et al. Phosphodiesterase-4 inhibition combined with isoniazid treatment of rabbits with pulmonary tuberculosis reduces macrophage activation and lung pathology. Am. J. Pathol. 179, 289–301 (2011).
Via, L. E. et al. Infection dynamics and response to chemotherapy in a rabbit model of tuberculosis using [18F]2-fluoro-deoxy-D-glucose positron emission tomography and computed tomography. Antimicrob. Agents Chemother. 56, 4391–4402 (2012).
Michot, J. M., Seral, C., Van Bambeke, F., Mingeot-Leclercq, M. P. & Tulkens, P. M. Influence of efflux transporters on the accumulation and efflux of four quinolones (ciprofloxacin, levofloxacin, garenoxacin, and moxifloxacin) in J774 macrophages. Antimicrob. Agents Chemother. 49, 2429–2437 (2005).
Dutta, S. et al. Steady-state propofol brain:plasma and brain:blood partition coefficients and the effect-site equilibration paradox. Br. J. Anaesth. 81, 422–424 (1998).
Mackaness, G. B. The intracellular activation of pyrazinamide and nicotinamide. Am. Rev. Tuberc 74, 718–728 (1956).
Marcinkeviciene, J. A., Magliozzo, R. S. & Blanchard, J. S. Purification and characterization of the Mycobacterium smegmatis catalase-peroxidase involved in isoniazid activation. J. Biol. Chem. 270, 22290–22295 (1995).
Prideaux, B. et al. High-sensitivity MALDI–MRM–MS imaging of moxifloxacin distribution in tuberculosis-infected rabbit lungs and granulomatous lesions. Anal. Chem. 83, 2112–2118 (2011).
Prideaux, B. & Stoeckli, M. Mass spectrometry imaging for drug distribution studies. J. Prot. 75, 4999–5013 (2012).
Seeley, E. H. & Caprioli, R. M. 3D imaging by mass spectrometry: a new frontier. Anal. Chem. 84, 2105–2110 (2012).
Lenaerts, A. J. et al. Location of persisting mycobacteria in a Guinea pig model of tuberculosis revealed by r207910. Antimicrob. Agents Chemother. 51, 3338–3345 (2007).
Lin, P. L. et al. Metronidazole prevents reactivation of latent Mycobacterium tuberculosis infection in macaques. Proc. Natl Acad. Sci. USA 109, 14188–14193 (2012).
Gillespie, S. H., Basu, S., Dickens, A. L., O'Sullivan, D. M. & McHugh, T. D. Effect of subinhibitory concentrations of ciprofloxacin on Mycobacterium fortuitum mutation rates. J. Antimicrob. Chemother. 56, 344–348 (2005).
Mitchison, D. A. The search for new sterilizing anti-tuberculosis drugs. Front. Biosci. 9, 1059–1072 (2004).
Mitchison, D. & Davies, G. The chemotherapy of tuberculosis: past, present and future. Int. J. Tuberc Lung Dis. 16, 724–732 (2012).
Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Thorax 53, 536–548 (1998).
Ginsburg, A. S. et al. Emergence of fluoroquinolone resistance in Mycobacterium tuberculosis during continuously dosed moxifloxacin monotherapy in a mouse model. Antimicrob. Agents Chemother. 49, 3977–3979 (2005).
Colijn, C., Cohen, T., Ganesh, A. & Murray, M. Spontaneous emergence of multiple drug resistance in tuberculosis before and during therapy. PLoS ONE 6, e18327 (2011).
Weinstein, E. A. et al. Noninvasive determination of 2-[18F]- fluoroisonicotinic acid hydrazide pharmacokinetics by positron emission tomography in in Mycobacterium tuberculosis-infected mice. Antimicrob. Agents Chemother. 56, 6284–6290 (2012).
Liu, L. et al. Radiosynthesis and bioimaging of the tuberculosis chemotherapeutics isoniazid, rifampicin and pyrazinamide in baboons. J. Med. Chem. 53, 2882–2891 (2010).
Goutelle, S., Bourguignon, L., Jelliffe, R. W., Conte, J. E. Jr & Maire, P. Mathematical modeling of pulmonary tuberculosis therapy: insights from a prototype model with rifampin. J. Theor. Biol. 282, 80–92 (2011).
Mitchison, D. A. The action of antituberculosis drugs in short-course chemotherapy. Tubercle 66, 219–225 (1985).
Kelly, C., Jefferies, C. & Cryan, S. A. Targeted liposomal drug delivery to monocytes and macrophages. J. Drug Deliv. 2011, 727241 (2011).
Clemens, D. L. et al. Targeted intracellular delivery of antituberculosis drugs to Mycobacterium tuberculosis-infected macrophages via functionalized mesoporous silica nanoparticles. Antimicrob. Agents Chemother. 56, 2535–2545 (2012).
Griffiths, G., Nystrom, B., Sable, S. B. & Khuller, G. K. Nanobead-based interventions for the treatment and prevention of tuberculosis. Nature Rev. Microbiol. 8, 827–834 (2010).
Pinheiro, M., Lucio, M., Lima, J. L. & Reis, S. Liposomes as drug delivery systems for the treatment of TB. Nanomed. (Lond.) 6, 1413–1428 (2011).
De Lorenzo, S. et al. Efficacy and safety of meropenem–clavulanate added to linezolid-containing regimens in the treatment of MDR-/XDR-TB. Eur. Respir. J. 41, 1386–1392 (2013).
Payen, M. C. et al. Clinical use of the meropenem–clavulanate combination for extensively drug-resistant tuberculosis. Int. J. Tuberc Lung Dis. 16, 558–560 (2012).
Hand, W. L., Corwin, R. W., Steinberg, T. H. & Grossman, G. D. Uptake of antibiotics by human alveolar macrophages. Am. Rev. Respir. Dis. 129, 933–937 (1984).
Johnson, J. D., Hand, W. L., Francis, J. B., King-Thompson, N. & Corwin, R. W. Antibiotic uptake by alveolar macrophages. J. Lab Clin. Med. 95, 429–439 (1980).
Conte, J. E. et al. Effects of AIDS and gender on steady-state plasma and intrapulmonary ethambutol concentrations. Antimicrob. Agents Chemother. 45, 2891–2896 (2001).
Rodvold, K. A., Yoo, L. & George, J. M. Penetration of anti-infective agents into pulmonary epithelial lining fluid: focus on antifungal, antitubercular and miscellaneous anti-infective agents. Clin. Pharmacokinet. 50, 689–704 (2011).
Ziglam, H. M., Baldwin, D. R., Daniels, I., Andrew, J. M. & Finch, R. G. Rifampicin concentrations in bronchial mucosa, epithelial lining fluid, alveolar macrophages and serum following a single 600 mg oral dose in patients undergoing fibre-optic bronchoscopy. J. Antimicrob. Chemother. 50, 1011–1015 (2002).
Soman, A., Honeybourne, D., Andrews, J., Jevons, G. & Wise, R. Concentrations of moxifloxacin in serum and pulmonary compartments following a single 400 mg oral dose in patients undergoing fibre-optic bronchoscopy. J. Antimicrob. Chemother. 44, 835–838 (1999).
Andrews, J. M. et al. Concentrations of levofloxacin (HR 355) in the respiratory tract following a single oral dose in patients undergoing fibre-optic bronchoscopy. J. Antimicrob. Chemother. 40, 573–577 (1997).
Schuler, P. et al. Penetration of sparfloxacin and ciprofloxacin into alveolar macrophages, epithelial lining fluid, and polymorphonuclear leucocytes. Eur. Respir. J. 10, 1130–1136 (1997).
Van de Velde, S. et al. Contrasting effects of human THP-1 cell differentiation on levofloxacin and moxifloxacin intracellular accumulation and activity against Staphylococcus aureus and Listeria monocytogenes. J. Antimicrob. Chemother. 62, 518–521 (2008).
Sacchettini, J. C., Rubin, E. J. & Freundlich, J. S. Drugs versus bugs: in pursuit of the persistent predator Mycobacterium tuberculosis. Nature Rev. Microbiol. 6, 41–52 (2008).
Sarathy, J., Dartois, V., Dick, T. & Gengenbacher, M. Reduced drug uptake in phenotypically resistant nutrient-starved non-replicating Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 57, 1648–1653 (2013).
Escribano, I. et al. Importance of the efflux pump systems in the resistance of Mycobacterium tuberculosis to fluoroquinolones and linezolid. Chemotherapy 53, 397–401 (2007).
Louw, G. E. et al. Rifampicin reduces susceptibility to ofloxacin in rifampicin-resistant Mycobacterium tuberculosis through efflux. Am. J. Respir. Crit. Care Med. 184, 269–276 (2011).
Sarathy, J. P., Lee, E. & Dartois, V. Polyamines inhibit porin-mediated fluoroquinolone uptake in mycobacteria. PLoS ONE 8, e65806 (2013).
Babbar, N. & Gerner, E. W. Targeting polyamines and inflammation for cancer prevention. Recent Results Cancer Res. 188, 49–64 (2011).
Clarke, J. R. & Tyms, A. S. Polyamine biosynthesis in cells infected with different clinical isolates of human cytomegalovirus. J. Med. Virol. 34, 212–216 (1991).
Hirsch, J. G. & Dubos, R. J. The effect of spermine on tubercle bacilli. J. Exp. Med. 95, 191–208 (1952).
Adams, K. N. et al. Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell 145, 39–53 (2011).
Zhang, Y. & Mitchison, D. The curious characteristics of pyrazinamide: a review. Int. J. Tuberc Lung Dis. 7, 6–21 (2003).
Shi, W. et al. Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis. Science 333, 1630–1632 (2011).
Zimhony, O., Cox, J. S., Welch, J. T., Vilcheze, C. & Jacobs, W. R. Jr. Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis. Nature Med. 6, 1043–1047 (2000).
Argyrou, A., Jin, L., Siconilfi-Baez, L., Angeletti, R. H. & Blanchard, J. S. Proteome-wide profiling of isoniazid targets in Mycobacterium tuberculosis. Biochemistry 45, 13947–13953 (2006).
Nishida, C. R. & Ortiz de Montellano, P. R. Bioactivation of antituberculosis thioamide and thiourea prodrugs by bacterial and mammalian flavin monooxygenases. Chem. Biol. Interact. 192, 21–25 (2011).
Wakamoto, Y. et al. Dynamic persistence of antibiotic-stressed mycobacteria. Science 339, 91–95 (2013).
Singh, R. et al. PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science 322, 1392–1395 (2008).
Chakraborty, S., Gruber, T., Barry, C. E. 3rd, Boshoff, H. I. & Rhee, K. Y. Para-aminosalicylic acid acts as an alternative substrate of folate metabolism in Mycobacterium tuberculosis. Science 339, 88–91 (2013).
Finley, S. D., Broadbelt, L. J. & Hatzimanikatis, V. Computational framework for predictive biodegradation. Biotechnol. Bioeng. 104, 1086–1097 (2009).
Fox, W., Ellard, G. A. & Mitchison, D. A. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946–1986, with relevant subsequent publications. Int. J. Tuberc Lung Dis. 3, S231–S279 (1999).
Subbian, S. et al. Spontaneous latency in a rabbit model of pulmonary tuberculosis. Am. J. Pathol. 181, 1711–1724 (2012).
Cohen, T. & Murray, M. Modeling epidemics of multidrug-resistant M. tuberculosis of heterogeneous fitness. Nature Med. 10, 1117–1121 (2004).
Zainuddin, Z. F. & Dale, J. W. Does Mycobacterium tuberculosis have plasmids? Tubercle 71, 43–49 (1990).
Ramaswamy, S. & Musser, J. M. Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update. Tuber Lung Dis. 79, 3–29 (1998).
Gupta, R. & Espinal, M. A prioritised research agenda for DOTS-Plus for multidrug-resistant tuberculosis (MDR-TB). Int. J. Tuberc Lung Dis. 7, 410–414 (2003).
Migliori, G. B. et al. Clinical and operational value of the extensively drug-resistant tuberculosis definition. Eur. Respir. J. 30, 623–626 (2007).
Nathan, C. Fresh approaches to anti-infective therapies. Sci Transl Med 4, 140sr2 (2012).
Gomez, J. E. & McKinney, J. D. M. tuberculosis persistence, latency, and drug tolerance. Tuberculosis (Edinb.) 84, 29–44 (2004).
Mitchison, D. A., Jindani, A., Davies, G. R. & Sirgel, F. Isoniazid activity is terminated by bacterial persistence. J. Infect. Dis. 195, 1871–1873 (2007).
Levin, B. R. & Rozen, D. E. Non-inherited antibiotic resistance. Nature Rev. Microbiol. 4, 556–562 (2006).
Dartois, V., Leong, F. J. & Dick, T. in Drug Discovery in Infectious Diseases. (ed. Seltzer, P.) 415–440 (Wiley-VCH, 2009).
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).
The author declares no competing financial interests.
- 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.
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.
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).
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.
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.
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.
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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