Drugs versus bugs: in pursuit of the persistent predator Mycobacterium tuberculosis

Tuberculosis (TB) claims a life every 10 seconds and global mortality rates are increasing despite the use of chemotherapy. But why have we not progressed towards the eradication of the disease? There is no simple answer, although apathy, politics, poverty and our inability to fight the chronic infection have all contributed. Drug resistance and HIV-1 are also greatly influencing the current TB battle plans, as our understanding of their complicity grows. In this Review, recent efforts to fight TB will be described, specifically focusing on how drug discovery could combat the resistance and persistence that make TB worthy of the moniker 'The Great White Plague'.

[1]  D. Mitchison,et al.  In vitro properties of rifapentine (MDL473) relevant to its use in intermittent chemotherapy of tuberculosis. , 1987, Tubercle.

[2]  C. Vilchèze,et al.  Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves the target of isoniazid , 2006, Nature Medicine.

[3]  P. Martín-Dávila,et al.  Linezolid for the treatment of multidrug-resistant tuberculosis. , 2005, The Journal of antimicrobial chemotherapy.

[4]  Sujata Sharma,et al.  Structure of isocitrate lyase, a persistence factor of Mycobacterium tuberculosis , 2000, Nature Structural Biology.

[5]  K. Andries,et al.  Genetic Basis for Natural and Acquired Resistance to the Diarylquinoline R207910 in Mycobacteria , 2006, Antimicrobial Agents and Chemotherapy.

[6]  T. Shim,et al.  Efficacy and tolerability of daily-half dose linezolid in patients with intractable multidrug-resistant tuberculosis. , 2006, The Journal of antimicrobial chemotherapy.

[7]  L. Jia,et al.  Pharmacodynamics and pharmacokinetics of SQ109, a new diamine‐based antitubercular drug , 2005, British journal of pharmacology.

[8]  E. Muñoz-Elías,et al.  Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence , 2005, Nature Medicine.

[9]  M. Botta,et al.  Ligand‐Based Virtual Screening, Parallel Solution‐Phase and Microwave‐Assisted Synthesis as Tools to Identify and Synthesize New Inhibitors of Mycobacterium tuberculosis , 2006, ChemMedChem.

[10]  A. Hopkins,et al.  The druggable genome , 2002, Nature Reviews Drug Discovery.

[11]  W. Burman,et al.  Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy. , 2001, American journal of respiratory and critical care medicine.

[12]  L. Toll,et al.  Synthesis and antitubercular activity of phenothiazines with reduced binding to dopamine and serotonin receptors. , 2007, Bioorganic & medicinal chemistry letters.

[13]  D. Eisenberg,et al.  High throughput crystallography of TB drug targets. , 2007, Infectious disorders drug targets.

[14]  A. Hopkins,et al.  Navigating chemical space for biology and medicine , 2004, Nature.

[15]  P. Hopewell,et al.  Imipenem for Treatment of Tuberculosis in Mice and Humans , 2005, Antimicrobial Agents and Chemotherapy.

[16]  Carolyn Shoen,et al.  Gatifloxacin in combination with rifampicin in a murine tuberculosis model. , 2007, The Journal of antimicrobial chemotherapy.

[17]  S. Meroueh,et al.  Bacterial Resistance to β‐Lactam Antibiotics: Compelling Opportunism, Compelling Opportunity , 2005 .

[18]  L. Wayne,et al.  Metronidazole is bactericidal to dormant cells of Mycobacterium tuberculosis , 1994, Antimicrobial Agents and Chemotherapy.

[19]  P. S. Murthy,et al.  Antitubercular activity of trifluoperazine, a calmodulin antagonist. , 1992, FEMS microbiology letters.

[20]  Yves L Janin,et al.  Antituberculosis drugs: ten years of research. , 2007, Bioorganic & medicinal chemistry.

[21]  L. Amaral,et al.  Activity of phenothiazines against antibiotic-resistant Mycobacterium tuberculosis: a review supporting further studies that may elucidate the potential use of thioridazine as anti-tuberculosis therapy. , 2001, The Journal of antimicrobial chemotherapy.

[22]  J. Kilburn,et al.  In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents , 1996, Antimicrobial agents and chemotherapy.

[23]  D. Pompliano,et al.  Drugs for bad bugs: confronting the challenges of antibacterial discovery , 2007, Nature Reviews Drug Discovery.

[24]  W. Sirawaraporn,et al.  Cloning and Expression of Mycobacterium tuberculosis and Mycobacterium leprae Dihydropteroate Synthase in Escherichia coli , 1999, Journal of bacteriology.

[25]  J. Rotschafer,et al.  Application of fluoroquinolone pharmacodynamics. , 2000, The Journal of antimicrobial chemotherapy.

[26]  H. Rubin,et al.  Inhibitors of type II NADH:menaquinone oxidoreductase represent a class of antitubercular drugs. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Jürgen Bajorath,et al.  Integration of virtual and high-throughput screening , 2002, Nature Reviews Drug Discovery.

[28]  R. Sood,et al.  Activity of RBx 7644 and RBx 8700, new investigational oxazolidinones, against Mycobacterium tuberculosis infected murine macrophages. , 2005, International journal of antimicrobial agents.

[29]  H. McIlleron,et al.  Determinants of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol Pharmacokinetics in a Cohort of Tuberculosis Patients , 2006, Antimicrobial Agents and Chemotherapy.

[30]  Brian K. Shoichet,et al.  Virtual screening of chemical libraries , 2004, Nature.

[31]  J. Irwin,et al.  Lead discovery using molecular docking. , 2002, Current opinion in chemical biology.

[32]  Clifton E. Barry,et al.  A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis , 2000, Nature.

[33]  M. Matsumoto,et al.  Synthesis and antituberculosis activity of a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles. , 2006, Journal of medicinal chemistry.

[34]  B. von der Lippe,et al.  Efficacy and safety of linezolid in multidrug resistant tuberculosis (MDR-TB)--a report of ten cases. , 2006, The Journal of infection.

[35]  C. Vilchèze,et al.  Crystal Structure of the Mycobacterium tuberculosis Enoyl-ACP Reductase, InhA, in Complex with NAD+ and a C16 Fatty Acyl Substrate* , 1999, The Journal of Biological Chemistry.

[36]  M. Pavelka,et al.  Genetic analysis of the β-lactamases of Mycobacterium tuberculosis and Mycobacterium smegmatis and susceptibility to β-lactam antibiotics , 2005 .

[37]  James C. Sacchettini,et al.  Mechanism of thioamide drug action against tuberculosis and leprosy , 2007, The Journal of experimental medicine.

[38]  Daniel R. Caffrey,et al.  Structure-based maximal affinity model predicts small-molecule druggability , 2007, Nature Biotechnology.

[39]  Lin Ting‐Wan,et al.  Mycobacterium tuberculosisの必須アシル‐CoAカルボキシラーゼカルボキシルトランスフェラーゼドメインAccD5の構造依存阻害剤デザイン , 2006 .

[40]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. , 2001, Advanced drug delivery reviews.

[41]  Ashutosh Kumar,et al.  Ligand based virtual screening and biological evaluation of inhibitors of chorismate mutase (Rv1885c) from Mycobacterium tuberculosis H37Rv. , 2007, Bioorganic & medicinal chemistry letters.

[42]  Conrad C. Huang,et al.  UCSF Chimera—A visualization system for exploratory research and analysis , 2004, J. Comput. Chem..

[43]  Matthew W Vetting,et al.  Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid , 2006, Nature Structural &Molecular Biology.

[44]  B. Robertson,et al.  Tetracycline-inducible gene regulation in mycobacteria , 2005, Nucleic acids research.

[45]  S. J. Brickner,et al.  Synthesis and antibacterial activity of U-100592 and U-100766, two oxazolidinone antibacterial agents for the potential treatment of multidrug-resistant gram-positive bacterial infections. , 1996, Journal of medicinal chemistry.

[46]  Ping Chen,et al.  Identification of new diamine scaffolds with activity against Mycobacterium tuberculosis. , 2006, Journal of medicinal chemistry.

[47]  C. Sohaskey,et al.  Nonreplicating persistence of mycobacterium tuberculosis. , 2001, Annual review of microbiology.

[48]  M. Falagas,et al.  Linezolid for the treatment of patients with [corrected] mycobacterial infections [corrected] a systematic review. , 2007, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[49]  Dale E. Johnson,et al.  Computational toxicology: heading toward more relevance in drug discovery and development. , 2006, Current opinion in drug discovery & development.

[50]  J. Sacchettini,et al.  Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis , 1995, Science.

[51]  T. Ohashi,et al.  Effect of a new rifamycin derivative, rifalazil, on liver microsomal enzyme induction in rat and dog. , 1998, Xenobiotica; the fate of foreign compounds in biological systems.

[52]  R. Shepherd,et al.  Antituberculous Agents. III. (+)-2,2 -(Ethylenediimino)-di-1-butanol1,2 and Some Analogs , 1962 .

[53]  K. Andries,et al.  Combinations of R207910 with Drugs Used To Treat Multidrug-Resistant Tuberculosis Have the Potential To Shorten Treatment Duration , 2006, Antimicrobial Agents and Chemotherapy.

[54]  Marianne Terrot,et al.  Combinatorial lead optimization of [1,2]-diamines based on ethambutol as potential antituberculosis preclinical candidates. , 2003, Journal of combinatorial chemistry.

[55]  Solomon Nwaka,et al.  Innovative lead discovery strategies for tropical diseases , 2006, Nature Reviews Drug Discovery.

[56]  Clifton E. Barry,et al.  Tuberculosis — metabolism and respiration in the absence of growth , 2005, Nature Reviews Microbiology.

[57]  E. Rubin,et al.  The folate pathway is a target for resistance to the drug para‐aminosalicylic acid (PAS) in mycobacteria , 2004, Molecular microbiology.

[58]  T. Myers,et al.  The Transcriptional Responses of Mycobacterium tuberculosis to Inhibitors of Metabolism , 2004, Journal of Biological Chemistry.

[59]  E. Giamarellos‐Bourboulis,et al.  Pharmacokinetic interactions of ceftazidime, imipenem and aztreonam with amikacin in healthy volunteers. , 2004, International journal of antimicrobial agents.

[60]  E. Rubin,et al.  Differential Antibiotic Susceptibilities of Starved Mycobacterium tuberculosis Isolates , 2005, Antimicrobial Agents and Chemotherapy.

[61]  Birgit Quinting,et al.  Crystal Structure of the Mycobacterium fortuitum Class A β-Lactamase: Structural Basis for Broad Substrate Specificity , 2006, Antimicrobial Agents and Chemotherapy.

[62]  N. Vishvanathan,et al.  In vitro and in vivo activities of the nitroimidazole CGI 17341 against Mycobacterium tuberculosis , 1993, Antimicrobial Agents and Chemotherapy.

[63]  R. Scotti,et al.  Antibacterial activity of DL 473, a new semisynthetic rifamycin derivative. , 1981, The Journal of antibiotics.

[64]  L. Hollister,et al.  Chlorpromazine in nonpsychotic patients with pulmonary tuberculosis. , 1960, The American review of respiratory disease.

[65]  S. Waksman,et al.  Effect of Streptomycin and Other Antibiotic Substances upon Mycobacterium tuberculosis and Related Organisms.∗,† , 1944 .

[66]  K. Watanabe,et al.  Synthesis and biological activity of 3'-hydroxy-5'-aminobenzoxazinorifamycin derivatives. , 1993, Chemical & pharmaceutical bulletin.

[67]  Shepherd Rg,et al.  ANTITUBERCULOUS AGENTS. II. N,N'-DIISOPROPYLETHYLENEDIAMINE AND ANALOGS. , 1962 .

[68]  M. Tsukamura,et al.  Therapeutic effect of a new antibacterial substance ofloxacin (DL8280) on pulmonary tuberculosis. , 2015, The American review of respiratory disease.

[69]  G M Pearl,et al.  Integration of computational analysis as a sentinel tool in toxicological assessments. , 2001, Current topics in medicinal chemistry.

[70]  S. Rajappa,et al.  Nitroimidazoles XXI 2,3-dihydro-6-nitroimidazo [2,1-b] oxazoles with antitubercular activity , 1989 .

[71]  William R. Jacobs,et al.  Complex lipid determines tissue-specific replication of Mycobacterium tuberculosis in mice , 1999, Nature.

[72]  N. Qureshi,et al.  Biosynthesis of C30 to C56 fatty acids by an extract of Mycobacterium tuberculosis H37Ra , 1984, Journal of bacteriology.

[73]  B. Gicquel,et al.  Identification of a virulence gene cluster of Mycobacterium tuberculosis by signature‐tagged transposon mutagenesis , 1999, Molecular microbiology.

[74]  H. Tomioka,et al.  Mechanism of action of antimycobacterial activity of the new benzoxazinorifamycin KRM-1648 , 1995, Antimicrobial agents and chemotherapy.

[75]  M. Spigelman,et al.  New tuberculosis therapeutics: a growing pipeline. , 2007, The Journal of infectious diseases.

[76]  M. Pavelka,et al.  Characterization of Novel Mycobacterium tuberculosis and Mycobacterium smegmatis Mutants Hypersusceptible to β-Lactam Antibiotics , 2005, Journal of bacteriology.

[77]  David Alland,et al.  Targeting Tuberculosis and Malaria through Inhibition of Enoyl Reductase , 2003, Journal of Biological Chemistry.

[78]  A. Mankin,et al.  Cross-linking in the Living Cell Locates the Site of Action of Oxazolidinone Antibiotics* , 2003, Journal of Biological Chemistry.

[79]  M. Hediger.  Design, synthesis, and evaluation of aza inhibitors of chorismate mutase. , 2004, Bioorganic & medicinal chemistry.

[80]  P. Carroll,et al.  Use of a Tetracycline-Inducible System for Conditional Expression in Mycobacterium tuberculosis and Mycobacterium smegmatis , 2005, Applied and Environmental Microbiology.

[81]  J. Molnár,et al.  Clinical Concentrations of Thioridazine Kill Intracellular Multidrug-Resistant Mycobacterium tuberculosis , 2003, Antimicrobial Agents and Chemotherapy.

[82]  L. Hollister,et al.  Chlorpromazine in Nonpsychotic Patients with Pulmonary Tuberculosis1 , 1960 .

[83]  Tanya Parish,et al.  The common aromatic amino acid biosynthesis pathway is essential in Mycobacterium tuberculosis. , 2002, Microbiology.

[84]  D. I. Edwards.  Mechanism of antimicrobial action of metronidazole. , 1979, The Journal of antimicrobial chemotherapy.

[85]  Ramón García-Domenech,et al.  Search of Chemical Scaffolds for Novel Antituberculosis Agents , 2005, Journal of biomolecular screening.

[86]  Pierre Baldi,et al.  Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase carboxyltransferase domain of Mycobacterium tuberculosis. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[87]  Feng Wang,et al.  Crystal Structure and Activity Studies of the Mycobacterium tuberculosis β-Lactamase Reveal Its Critical Role in Resistance to β-Lactam Antibiotics , 2006, Antimicrobial Agents and Chemotherapy.

[88]  S. Furney,et al.  Metronidazole Therapy in Mice Infected with Tuberculosis , 1999, Antimicrobial Agents and Chemotherapy.

[89]  S. Franzblau,et al.  Synthesis and antitubercular activity of quaternized promazine and promethazine derivatives. , 2007, Bioorganic & medicinal chemistry letters.

[90]  A. J. Crowle,et al.  Chlorpromazine: a drug potentially useful for treating mycobacterial infections. , 1992, Chemotherapy.

[91]  W. Burman,et al.  Comparative Pharmacokinetics and Pharmacodynamics of the Rifamycin Antibacterials , 2001, Clinical pharmacokinetics.

[92]  Graham R. Stewart,et al.  Tuberculosis: a problem with persistence , 2003, Nature Reviews Microbiology.

[93]  L. Dittert,et al.  Pharmacokinetics of kanamycin following intramuscular administration , 1973, Journal of Pharmacokinetics and Biopharmaceutics.

[94]  Hinrich W. H. Göhlmann,et al.  A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis , 2005, Science.

[95]  J. Sacchettini,et al.  Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis. , 1998, Science.

[96]  John L. Johnson,et al.  Safety and Bactericidal Activity of Rifalazil in Patients with Pulmonary Tuberculosis , 2001, Antimicrobial Agents and Chemotherapy.

[97]  M. Spigelman,et al.  Challenges in tuberculosis drug research and development , 2007, Nature Medicine.

[98]  S. Cole,et al.  The catalase—peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis , 1992, Nature.

[99]  Peter J Tonge,et al.  High affinity InhA inhibitors with activity against drug-resistant strains of Mycobacterium tuberculosis. , 2006, ACS chemical biology.

[100]  Dirk Bald,et al.  Diarylquinolines target subunit c of mycobacterial ATP synthase. , 2007, Nature chemical biology.

[101]  Rossella Fioravanti,et al.  Bactericidal Activities of the Pyrrole Derivative BM212 against Multidrug-Resistant and Intramacrophagic Mycobacterium tuberculosis Strains , 1998, Antimicrobial Agents and Chemotherapy.

[102]  E. Goldstein,et al.  Two decades of imipenem therapy. , 2006, The Journal of antimicrobial chemotherapy.

[103]  K. Duncan,et al.  Current strategies for identifying and validating targets for new treatment-shortening drugs for TB. , 2007, Current molecular medicine.

[104]  V. Jarlier,et al.  Novel Gyrase Mutations in Quinolone-Resistant and -Hypersusceptible Clinical Isolates of Mycobacterium tuberculosis: Functional Analysis of Mutant Enzymes , 2006, Antimicrobial Agents and Chemotherapy.

[105]  T. Weisbrod,et al.  Efflux pump of the proton antiporter family confers low-level fluoroquinolone resistance in Mycobacterium smegmatis. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[106]  T. Weisbrod,et al.  Characterization of the Mycobacterium tuberculosis iniBAC Promoter, a Promoter That Responds to Cell Wall Biosynthesis Inhibition , 2000, Journal of bacteriology.

[107]  H. Nikaido,et al.  Can penicillins and other beta-lactam antibiotics be used to treat tuberculosis? , 1995, Antimicrobial agents and chemotherapy.

[108]  L. Amaral,et al.  Inhibition of the respiration of multi-drug resistant clinical isolates of Mycobacterium tuberculosis by thioridazine: potential use for initial therapy of freshly diagnosed tuberculosis. , 1996, The Journal of antimicrobial chemotherapy.

[109]  Sabine Ehrt,et al.  Controlling gene expression in mycobacteria with anhydrotetracycline and Tet repressor , 2005, Nucleic acids research.

[110]  P. Hopewell,et al.  Activity of amoxicillin/clavulanate in patients with tuberculosis. , 1998, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[111]  E. Rubin,et al.  Comprehensive identification of conditionally essential genes in mycobacteria , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[112]  David G. Russell,et al.  Who puts the tubercle in tuberculosis? , 2007, Nature Reviews Microbiology.

[113]  B. Barrell,et al.  Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence , 1998, Nature.

[114]  H. Tomioka,et al.  In vitro and in vivo activities of the benzoxazinorifamycin KRM-1648 against Mycobacterium tuberculosis , 1995, Antimicrobial agents and chemotherapy.

[115]  H. Drugeon,et al.  Comparison of the in vitro activities of rifapentine and rifampicin against Mycobacterium tuberculosis complex. , 2000, The Journal of antimicrobial chemotherapy.

[116]  M. Matsumoto,et al.  OPC-67683, a Nitro-Dihydro-Imidazooxazole Derivative with Promising Action against Tuberculosis In Vitro and In Mice , 2006, PLoS medicine.

[117]  R. Angeletti,et al.  Proteome-wide profiling of isoniazid targets in Mycobacterium tuberculosis. , 2006, Biochemistry.

[118]  S. Waksman,et al.  Streptomycin, a Substance Exhibiting Antibiotic Activity Against Gram-Positive and Gram-Negative Bacteria.∗† , 1944, Clinical orthopaedics and related research.

[119]  David Eisenberg,et al.  A Novel Inhibitor of Mycobacterium tuberculosis Pantothenate Synthetase , 2007, Journal of biomolecular screening.

[120]  Karl W. Broman,et al.  A postgenomic method for predicting essential genes at subsaturation levels of mutagenesis: Application to Mycobacterium tuberculosis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[121]  F. Brossier,et al.  Treatment failure in a case of extensively drug-resistant tuberculosis associated with selection of a GyrB mutant causing fluoroquinolone resistance , 2007, European Journal of Clinical Microbiology & Infectious Diseases.

[122]  H. Hänel,et al.  Nitroheterocyclic drugs with broad spectrum activity , 2003, Parasitology Research.

[123]  W. Bishai,et al.  Bactericidal Activity of the Nitroimidazopyran PA-824 in a Murine Model of Tuberculosis , 2005, Antimicrobial Agents and Chemotherapy.

[124]  J. Norton,et al.  Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium tuberculosis. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[125]  W. Bishai,et al.  Combination Chemotherapy with the Nitroimidazopyran PA-824 and First-Line Drugs in a Murine Model of Tuberculosis , 2006, Antimicrobial Agents and Chemotherapy.

[126]  F. López-Muñoz,et al.  History of the discovery and clinical introduction of chlorpromazine. , 2005, Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists.

[127]  W. Kingston.  Streptomycin, Schatz v. Waksman, and the Balance of Credit for Discovery , 2004, Journal of the history of medicine and allied sciences.

[128]  M. Cynamon,et al.  Activity of KRM-1648 in combination with isoniazid against Mycobacterium tuberculosis in a murine model , 1996, Antimicrobial agents and chemotherapy.