Enzymes that participate in the FAS I and II pathways in
Abstract
Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb), is the main cause of death due to an infectious disease. After more than 100 years of the discovery of Mtb, clinicians still face difficulties finding an effective treatment for the increasing number of drug-resistant cases. The difficulties in the clinical setting can be related to the slow pace at which the understanding of the physiology of this bacterium has occurred. Mtb is distinct from other microorganisms not only due to its slow growth and difficulties to study in the laboratory, but also due to its inherent physiology such as its complex cell envelope and its metabolic pathways. Understanding the physiology of drug susceptible and resistant Mtb strains is crucial for the design of an effective chemotherapy against TB. This chapter will review the mycobacterial cell envelope and major physiological pathways together with recent discoveries in Mtb drug resistance through different “omics” disciplines.
Keywords
- drug resistance
- physiology
- systems biology
- proteomics
- genomics
- lipidomics
1. Introduction
The history of tuberculosis (TB), the disease caused by
2. Review of Mtb major metabolic pathways and cell envelope
2.1. Major central metabolic pathways in Mtb
2.2. Lipid metabolism: β-oxidation and fatty acid synthesis
Lipid metabolism is a highly relevant physiologic process in
2.2.1. Fatty acid degradation
Fatty acid catabolism in
2.2.2. Fatty acid synthesis
The complexity of
Description | Gene | Rv number | Enzyme |
---|---|---|---|
FAS I | 2524 | Fatty acid synthetase | |
Transition FAS I to FAS II | 2243 | Malonyl-CoA ACP transacylase | |
2247 | Acetyl/propionyl-CoA carboxylase (beta subunit) | ||
2244 | Acyl carrier protein | ||
0533 | β-Ketoacyl-ACP synthase III | ||
FAS II | 2245/2246 | β-Ketoacyl-ACP synthase | |
1483 | β-Ketoacyl-ACP reductase | ||
0635/0636/0637 | (3)-hydroxyacyl-ACP dehydratase subunit A/B/C | ||
0241 | 3-hydroxyacyl-thioester dehydratase | ||
1142/1141 | Currently annotated as a enoyl-CoA hydratase, but proposed to be 2-trans-enoyl-ACP isomerase | ||
1484 | 2-trans-enoyl-ACP reductase | ||
Modifications | |||
Desaturases | 0824/1094/3229 | Acyl carrier protein desaturase | |
Methyltransferases (methylation, oxygen function introduction and cyclopropanation) | 0645c | Methoxymycolic acid synthase 1 | |
0644c | Methoxymycolic acid synthase 2 (distal cyclopropane in α-MA, proximal cis-cyclopropane in keto-MA) | ||
0643c | Methoxymycolic acid synthase 3 (oxygenated MA) | ||
0642c | Methoxy mycolic acid synthase 4 (oxygenated MA) | ||
3392c | Cyclopropane-fatty-acyl-phospholipid synthase 1 (distal position) | ||
0503c | Cyclopropane-fatty-acyl-phospholipid synthase 2 (proximal position-specific in methoxy-MA) | ||
Mycolic acid modification | 0470c | Mycolic acid synthase (proximal cyclopropanation function α-MA) | |
0469 | Mycolic acid synthase | ||
Clainsen-type condensation | 3799c | Acyl-CoA carboxylase | |
3280 | Acyl-CoA carboxylase | ||
3801 | Fatty-acid-AMP ligase | ||
3800 | Polyketide synthase-13 | ||
Mycolic acid processing | 0206 | Transmembrane transport protein-3 | |
3802 | Proposed to be a Mycolyltransferase I, recently shown to have phospholipase and thioesterase activity | ||
2509 | Reductase | ||
3804c/1886c/0129c | Fibronectin-binding protein ABC or antigen 85 complex |
There are important aspects to highlight regarding FAS I and II in
Regarding FAS II specifically, this pathway is involved in fatty acid elongation instead of
The meromycolate chain resulting from FAS II cycle can be “decorated” with chemical modifications such as cyclopropanations and methylations that are introduced before the second Claisen-type reaction occurs. These modifications can be at distal or proximal positions and are carried out by S-adenosyl-methionine (SAM)-dependent methyl transferases (Table 1). Unsaturations on the other hand, are proposed to occur differently under aerobic or anaerobic conditions. The method of double bond introduction in mycolic acid in
After the modification in the meromycolate chain and the last condensation reaction occur, a mycolic acid (either α-, keto, or methoxymycolic acid) molecule is formed and can be attached to a trehalose molecule by the action of the Corynebacterineae mycolate reductase A, encoded by Rv2509 (also known CmrA) [15]. Once the mycolic acid is covalently linked with trehalose to form trehalose monomycolate (TMM), it is transported to the cell wall by the protein MmpL3 [16]. TMM is then the source of the mycolyl group for arabinogalactan and for other TMMs in the cell wall, generating trehalose dimycolate (TDM); in a reaction catalyzed by the fibronectin-binding proteins (Fbp) ABC ([17], reviewed in Refs. [14, 18]). Much of the understanding of the FAS I and II routes has been based on sequence homology with reference bacterial strains and mutation analysis using model organism such as
2.3. Redox metabolism
In general, reduction-oxidation (i.e. redox) reactions are highly relevant for
Intracellular or exogenously originated reactive oxygen species (ROS) and RNI have the potential to damage lipids, DNA, and proteins by oxidation, peroxidation, and nitration reactions [23], which can result in protein inactivation, and alteration of both cell organization and signal transduction. Therefore, it is crucial to successfully maintain redox homeostasis to keep the integrity of the cell. Intracellularly, the changes in the redox and nutrient levels are sensed by WhiB proteins (WhiB1-7) while extracellularly different molecules such as nitric oxide (NO), carbon monoxide (CO), and H2O2. The reduced and oxidized forms of the nicotinamide adenine dinucleotide (NADH/NAD+) can work as sensors that induce a direct transcriptional response or indirectly alter transcription through a two-component regulatory system such as DosRS-DosRT [2, 21]. Moreover, different bacterial enzymes participate in the neutralization of the host-induced ROI and NOI such as superoxide dismutase (SodA), catalase-peroxidase (KatG), and the antioxidant complex formed by alkyl-hydroperoxidases (AhpC and AhpD), dihydrolipoamide acyltransferase (DlaT), and dehydrogenase (LpdC). Other enzymes in the redox metabolism include the peroxiredoxins (AhpE, TPx, Bcp, and BcpB) and thioredoxins (TrxA, B, and C).
Of these, KatG also plays a central role in
As discussed above, redox reactions play an important role in bacterial respiration. In the next section, details about the cellular respiration process in
2.4. Respiration in Mtb
Given the dynamic
Most of the
Contrary to aerobic respiration, mediators in
2.5. Mtb envelope
Moving to another important aspect of
The
The most external layer of
The
Mycolic acids are not unique structures of the
Finally, the plasmatic membrane includes different types of phospholipids such as phosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylinositol mannosides (PIMs). PIMs are mainly located in the outer leaflet. Other important components are the highly immunogenic lipoglycan lipoarabinomannan (LAM) and lipomannan [39]. Due to the high abundance of LAM in the
3. Mechanisms of drug resistance in Mtb
As is the case in other microorganisms, drug resistance in
Although a combined therapy for TB is normally effective for most cases, TB cases resistant to a subsection or all anti-TB drugs have been reported in clinical settings. Because INH and RIF are the most widely anti-TB drugs used, there is a higher frequency of mono-resistance to any of these drugs or to both drugs (INH and RIF, known as multidrug-resistance TB or MDR-TB) among drug-resistant
3.1. INH resistance
In 1951, the anti-TB properties of a new drug, INH, were reported. This was a critical event in TB history that was optimistically described as the “new treatment for the white scourge.” Unfortunately, the appearance of INH-resistant (INHr) cases emerged the same year INH was introduced in medical practice [49]. INH resistance is one of the most common forms of drug-resistant TB. The resistance mechanism to this drug is multigenic and can be divided into three categories: prevention of drug activation, alteration of the target, and differential expression of the target. In the first group, mutations in
In the category of alteration of the target and increased expression of the target, mutations in the
3.2. RIF resistance
Followed the discovery of INH, rifampicin (RIF) was discovered in 1963 and reduced the anti-TB treatment from 18 to 9 months [62, 63, 64]. Currently, a shorter combined therapy with higher doses of rifampicin or isoniazid is being evaluated [65]. The rationale behind the increase dose of rifampicin is that the currently used dose of RIF was proposed in 1971 with the basis of generating a cost-effective treatment that was non-toxic for TB patients, albeit a study of the maximum dose of the drug tolerated in human has never been performed [66]. Recent studies in animal models have shown that higher doses of this drug could be effective even in shorter regimes, reducing also the probability to generate resistant microorganisms to the drug [66, 67, 68].
RIF resistance in
4. Impact of drug resistance in Mtb physiology as seen through proteomics perspective
Since there is a wider repertoire of INH resistance-conferring mutations compared with RIF resistance-conferring mutations (see Sections 3.1.1 and 3.1.2), a more variable phenotype in INHr strains compared to RIFr strains is expected. Additionally, the genetic lineage and background of each strain play an important role in the phenotype resultant after drug-resistance is acquired [69, 70, 71]. This is explained by the fact that compensatory mutations associated with some genetic backgrounds but not others may results in different competitive phenotypes. Our laboratory recently demonstrated that the same mutation causing INH resistance in two
Clonal
We have used comparative shotgun proteomics of different
4.1. “The isoniazid resistance case”: findings from katG mutant Mtb strain of the Beijing lineage through proteomics
Given the high frequency of
Consistent with previous studies, the global proteomics study of the Beijing clinical pair through LC-MS/MS demonstrated that the INHr strain had significantly reduced levels of KatG in three of the four subcellular fractions evaluated compared with its isogenic INHs progenitor. The fact that the levels of this protein were reduced in the soluble fractions (cytosol and secreted proteins) and the bacterial membrane is a clear indication that this INHr strain lacks its ability to activate INH. An additional 45 proteins were found with altered abundance; these protein changes may be a potential compensatory mechanisms related to the reduced KatG levels and its consequent impact on mycobacterial physiology and fitness [80].
Among the 45 proteins identified, proteins related to intermediary metabolism and respiration represented majority of differentially abundant between INHr and INHs strains. Among them, enzymes from the tricarboxylic acid (TCA) cycle (SucC, SucD, Mdh, Acn, and AceE) were all decreased in the INHr strain. Proteins related to lipid biosynthesis and degradation pathways also represented important differences between the strains, with mainly higher levels in the INHr strain. The proteins Fas, FabG4, and FbpD of the lipid biosynthetic pathway were increased. In the β-oxidation pathway, the dehydrogenases FadE22 and FadE32 and the acetyl-CoA acyltransferase FadA2 were increased, but the crotonases EchA9 and EchA21 were decreased in the INHr strain. Proteins in the virulence and detoxification category such DnaK and GroES were also increased in the INHr strain as well as the hypothetical protein Rv2204c. Finally, the transcription regulation proteins Crp and PrrA were also higher in the INHr strain compared to the INHs parental strain [80].
Interestingly, the INHr Beijing strain had the
A previous proteomic analysis using non-clonal
A recent virulence study of laboratory and clinical clonal pairs of
4.2. Acquisition of rifampicin (RIF) resistance in isogenic Mtb strains of the Beijing and Haarlem lineage
Phenotypic consequences of mutations in the
4.3. Study of multidrug resistance in Mtb trough proteomics
A handful of proteomic studies focused on the comparison of drug susceptible (DS) versus multidrug-resistant strains (MDR)
The proteomic analysis of non-genetically related
The analysis using non-genetically related strains provide valuable insights about the protein dynamics among DS and MDR
5. Lipidomics studies in Mtb drug-resistant strains
5.1. Lipidomics in INHr Mtb strains
Among the different scientific disciplines supporting biological research, metabolomics is the study of chemically diverse groups of biomolecules including sugars, nucleotides, peptides, lipids, among others; using technologies such as MS and nuclear magnetic resonance (NMR). Lipidomics is a branch of metabolomics that specializes on the water-insoluble metabolites—lipids. These are diverse metabolites that are part of the major molecules in the cell (particularly, in the cell membrane) [108]. In
Thus far, only one metabolomics study has been reported comparing
5.2. Lipidomics in RIFr Mtb strains
The lipidomics studies in RIF resistant
6. Closing remarks
The systematic study of
References
- 1.
Gouzy A, Poquet Y, Neyrolles O. Nitrogen metabolism in Mycobacterium tuberculosis physiology and virulence. Nature Reviews Microbiology. 2014;12 (11):729-737 - 2.
Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature. 1998;393 (6685):537-544 - 3.
Maksymiuk C, Balakrishnan A, Bryk R, Rhee KY, Nathan CF. E1 of alpha-ketoglutarate dehydrogenase defends Mycobacterium tuberculosis against glutamate anaplerosis and nitroxidative stress. Proceedings of the National Academy of Sciences of the United States of America. 2015;112 (43):E5834-E5843 - 4.
Rhee KY, de Carvalho LP, Bryk R, Ehrt S, Marrero J, Park SW, et al. Central carbon metabolism in Mycobacterium tuberculosis : An unexpected frontier. Trends in Microbiology. 2011;19 (7):307-314 - 5.
Tian J, Bryk R, Itoh M, Suematsu M, Nathan C. Variant tricarboxylic acid cycle in Mycobacterium tuberculosis : Identification of alpha-ketoglutarate decarboxylase. Proceedings of the National Academy of Sciences of the United States of America. 2005;102 (30):10670-10675 - 6.
Watanabe S, Zimmermann M, Goodwin MB, Sauer U, Barry CE, 3rd, Boshoff HI. Fumarate reductase activity maintains an energized membrane in anaerobic Mycobacterium tuberculosis . PLoS Pathogens. 2011;7 (10):e1002287 - 7.
Munoz-Elias EJ, McKinney JD. Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence. Nature Medicine. 2005;11 (6):638-644 - 8.
Baughn AD, Garforth SJ, Vilcheze C, Jacobs WR, Jr. An anaerobic-type alpha-ketoglutarate ferredoxin oxidoreductase completes the oxidative tricarboxylic acid cycle of Mycobacterium tuberculosis . PLoS Pathogens. 2009;5 (11):e1000662 - 9.
Cumming BM, Steyn AJ. Metabolic plasticity of central carbon metabolism protects mycobacteria. Proceedings of the National Academy of Sciences of the United States of America. 2015; 112 (43):13135-13136 - 10.
Munoz-Elias EJ, McKinney JD. Carbon metabolism of intracellular bacteria. Cellular Microbiology. 2006; 8 (1):10-22 - 11.
Williams KJ, Boshoff HI, Krishnan N, Gonzales J, Schnappinger D, Robertson BD. The Mycobacterium tuberculosis beta-oxidation genes echA5 and fadB3 are dispensable for growth in vitro and in vivo. Tuberculosis (Edinburgh, Scotland). 2011;91 (6):549-555 - 12.
Bhatt A, Molle V, Besra GS, Jacobs WR, Jr., Kremer L. The Mycobacterium tuberculosis FAS-II condensing enzymes: Their role in mycolic acid biosynthesis, acid-fastness, pathogenesis and in future drug development. Molecular Microbiology. 2007;64 (6):1442-1454 - 13.
Marrakchi H, Laneelle MA, Daffe M. Mycolic acids: Structures, biosynthesis, and beyond. Chemistry and Biology. 2014; 21 (1):67-85 - 14.
Takayama K, Wang C, Besra GS. Pathway to synthesis and processing of mycolic acids in Mycobacterium tuberculosis . Clinical Microbiology Reviews. 2005;18 (1):81-101 - 15.
Lea-Smith DJ, Pyke JS, Tull D, McConville MJ, Coppel RL, Crellin PK. The reductase that catalyzes mycolic motif synthesis is required for efficient attachment of mycolic acids to arabinogalactan. Journal of Biological Chemistry. 2007; 282 (15):11000-11008 - 16.
Belardinelli JM, Yazidi A, Yang L, Fabre L, Li W, Jacques B, et al. Structure-function profile of MmpL3, the essential mycolic acid transporter from Mycobacterium tuberculosis . ACS Infectious Diseases. 2016;2 (10):702-713 - 17.
Belisle JT, Vissa VD, Sievert T, Takayama K, Brennan PJ, Besra GS. Role of the major antigen of Mycobacterium tuberculosis in cell wall biogenesis. Science. 1997;276 (5317):1420-1422 - 18.
North EJ, Jackson M, Lee RE. New approaches to target the mycolic acid biosynthesis pathway for the development of tuberculosis therapeutics. Current Pharmaceutical Design. 2014; 20 (27):4357-4378 - 19.
Green J, Paget MS. Bacterial redox sensors. Nature Reviews Microbiology. 2004; 2 (12):954-966 - 20.
Kumar A, Farhana A, Guidry L, Saini V, Hondalus M, Steyn AC. Redox homeostasis in mycobacteria: The key to tuberculosis control? Expert Reviews in Molecular Medicine. 2011; 13 - 21.
Trivedi A, Singh N, Bhat SA, Gupta P, Kumar A. Redox biology of tuberculosis pathogenesis. Advances in Microbial Physiology. 2012; 60 :263-324 - 22.
Gengenbacher M, Kaufmann SH. Mycobacterium tuberculosis : Success through dormancy. FEMS Microbiology Review. 2012;36 (3):514-532 - 23.
Leichert LI, Scharf C, Hecker M. Global characterization of disulfide stress in Bacillus subtilis . Journal of Bacteriology. 2003;185 (6):1967-1975 - 24.
Bertrand T, Eady NA, Jones JN, Jesmin, Nagy JM, Jamart-Gregoire B, et al. Crystal structure of Mycobacterium tuberculosis catalase-peroxidase. Journal of Biological Chemistry. 2004; 279 (37):38991-38999 - 25.
Ghiladi RA, Medzihradszky KF, Rusnak FM, Ortiz de Montellano PR. Correlation between isoniazid resistance and superoxide reactivity in Mycobacterium tuberculosis KatG. Journal of the American Chemical Society. 2005;127 (38):13428-13442 - 26.
Wengenack NL, Jensen MP, Rusnak F, Stern MK. Mycobacterium tuberculosis KatG is a peroxynitritase. Biochemical and Biophysical Research Communications. 1999;256 (3):485-487 - 27.
Zhang Y, Heym B, Allen B, Young D, Cole S. The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis . Nature. 1992;358 (6387):591-593 - 28.
Manca C, Paul S, Barry CE, 3rd, Freedman VH, Kaplan G. Mycobacterium tuberculosis catalase and peroxidase activities and resistance to oxidative killing in human monocytes in vitro. Infection and Immunity. 1999;67 (1):74-79 - 29.
Ng VH, Cox JS, Sousa AO, MacMicking JD, McKinney JD. Role of KatG catalase-peroxidase in mycobacterial pathogenesis: Countering the phagocyte oxidative burst. Molecular Microbiology. 2004; 52 (5):1291-1302 - 30.
Boshoff HI, Barry CE, 3rd. Tuberculosis—Metabolism and respiration in the absence of growth. Nature Reviews Microbiology. 2005; 3 (1):70-80 - 31.
Cook GM, Hards K, Vilcheze C, Hartman T, Berney M. Energetics of respiration and oxidative phosphorylation in mycobacteria. Microbiology Spectrum. 2014; 2 (3) - 32.
Bald D, Koul A. Respiratory ATP synthesis: The new generation of mycobacterial drug targets? FEMS Microbiology Letters. 2010; 308 (1):1-7 - 33.
Koul A, Dendouga N, Vergauwen K, Molenberghs B, Vranckx L, Willebrords R, et al. Diarylquinolines target subunit c of mycobacterial ATP synthase. Nature Chemical Biology. 2007; 3 (6):323-324 - 34.
Jarlier V, Nikaido H. Mycobacterial cell wall: Structure and role in natural resistance to antibiotics. FEMS Microbiology Letters. 1994; 123 (1-2):11-18 - 35.
Daffe M, Draper P. The envelope layers of mycobacteria with reference to their pathogenicity. Advances in Microbial Physiology. 1998; 39 :131-203 - 36.
Minnikin DE. Chemical principles in the organization of lipid components in the mycobacterial cell envelope. Research in Microbiology. 1991; 142 (4):423-427 - 37.
Daffe M. The cell envelope of tubercle bacilli. Tuberculosis 2015; 95 :S155-S158 - 38.
Hunter RL, Olsen MR, Jagannath C, Actor JK. Multiple roles of cord factor in the pathogenesis of primary, secondary, and cavitary tuberculosis, including a revised description of the pathology of secondary disease. Annals of Clinical Laboratory Science. 2006; 36 (4):371-386 - 39.
Brennan PJ, Nikaido H. The envelope of mycobacteria. Annual Review of Biochemistry. 1995; 64 :29-63 - 40.
Crick DC, Mahapatra S, Brennan PJ. Biosynthesis of the arabinogalactan-peptidoglycan complex of Mycobacterium tuberculosis . Glycobiology. 2001;11 (9):107R-118R - 41.
Sartain MJ, Dick DL, Rithner CD, Crick DC, Belisle JT. Lipidomic analyses of Mycobacterium tuberculosis based on accurate mass measurements and the novel “Mtb LipidDB”. Journal of Lipid Research. 2011;52 (5):861-872 - 42.
Asselineau J, Lederer E. Structure of the mycolic acids of Mycobacteria. Nature. 1950; 166 (4227):782-783 - 43.
McNeil M, Daffe M, Brennan PJ. Location of the mycolyl ester substituents in the cell walls of mycobacteria. Journal of Biological Chemistry. 1991; 266 (20):13217-13223 - 44.
Besra GS, Sievert T, Lee RE, Slayden RA, Brennan PJ, Takayama K. Identification of the apparent carrier in mycolic acid synthesis. Proceedings of the National Academy of Sciences of the United States of America. 1994; 91 (26):12735-12739 - 45.
Shah M, Hanrahan C, Wang ZY, Dendukuri N, Lawn SD, Denkinger CM, et al. Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in HIV-positive adults. Cochrane Database of Systematic Reviews. 2016;(5):CD011420 - 46.
Soetaert K, Rens C, Wang XM, De Bruyn J, Laneelle MA, Laval F, et al. Increased vancomycin susceptibility in mycobacteria: A new approach to identify synergistic activity against multidrug-resistant mycobacteria. Antimicrobial Agents and Chemotherapy. 2015; 59 (8):5057-5060 - 47.
Almeida Da Silva PE, Palomino JC. Molecular basis and mechanisms of drug resistance in Mycobacterium tuberculosis : Classical and new drugs. Journal of Antimicrobial Chemotherapy. 2011;66 (7):1417-1430 - 48.
Organization WH. Global Tuberculosis Report. 2015 - 49.
Vilcheze C, Jacobs WR, Jr. The mechanism of isoniazid killing: Clarity through the scope of genetics. Annual Review of Microbiology. 2007; 61 :35-50 - 50.
Seifert M, Catanzaro D, Catanzaro A, Rodwell TC. Genetic mutations associated with isoniazid resistance in Mycobacterium tuberculosis : A systematic review. PLoS One. 2015;10 (3):e0119628 - 51.
Vilcheze C, Jacobs WR, Jr. Resistance to isoniazid and ethionamide in Mycobacterium tuberculosis : Genes, mutations, and causalities. Microbiology Spectrum. 2014;2 (4):MGM2-0014-2013 - 52.
Middlebrook G, Cohn ML. Some observations on the pathogenicity of isoniazid-resistant variants of tubercle bacilli. Science. 1953; 118 (3063):297-299 - 53.
Zhang Y, Garbe T, Young D. Transformation with katG restores isoniazid-sensitivity in Mycobacterium tuberculosis isolates resistant to a range of drug concentrations. Molecular Microbiology. 1993;8 (3):521-524 - 54.
Bergval IL, Schuitema AR, Klatser PR, Anthony RM. Resistant mutants of Mycobacterium tuberculosis selected in vitro do not reflect the in vivo mechanism of isoniazid resistance. Journal of Antimicrobial Chemotherapy. 2009;64 (3):515-523 - 55.
McGrath M, Gey van Pittius NC, van Helden PD, Warren RM, Warner DF. Mutation rate and the emergence of drug resistance in Mycobacterium tuberculosis . Journal of Antimicrobial Chemotherapy. 2014;69 (2):292-302 - 56.
Mdluli K, Swanson J, Fischer E, Lee RE, Barry CE, 3rd. Mechanisms involved in the intrinsic isoniazid resistance of Mycobacterium avium . Molecular Microbiology. 1998;27 (6):1223-1233 - 57.
Slayden RA, Barry CE, 3rd. The genetics and biochemistry of isoniazid resistance in Mycobacterium tuberculosis . Microbes and Infection. 2000;2 (6):659-669 - 58.
Larsen MH, Vilcheze C, Kremer L, Besra GS, Parsons L, Salfinger M, et al. Overexpression of inhA, but not kasA, confers resistance to isoniazid and ethionamide in Mycobacterium smegmatis ,M. bovis BCG andM. tuberculosis . Molecular Microbiology. 2002;46 (2):453-466 - 59.
Sandy J, Mushtaq A, Kawamura A, Sinclair J, Sim E, Noble M. The structure of arylamine N-acetyltransferase from Mycobacterium smegmatis —An enzyme which inactivates the anti-tubercular drug, isoniazid. Journal of Molecular Biology. 2002;318 (4):1071-1083 - 60.
Payton M, Auty R, Delgoda R, Everett M, Sim E. Cloning and characterization of arylamine N-acetyltransferase genes from Mycobacterium smegmatis andMycobacterium tuberculosis : Increased expression results in isoniazid resistance. Journal of Bacteriology. 1999;181 (4):1343-1347 - 61.
Dantes R, Metcalfe J, Kim E, Kato-Maeda M, Hopewell PC, Kawamura M, et al. Impact of isoniazid resistance-conferring mutations on the clinical presentation of isoniazid monoresistant tuberculosis. PLoS One. 2012; 7 (5):e37956 - 62.
Gill SK, Garcia GA. Rifamycin inhibition of WT and Rif-resistant Mycobacterium tuberculosis andEscherichia coli RNA polymerases in vitro. Tuberculosis (Edinburgh, Scotland). 2011;91 (5):361-369 - 63.
Campbell EA, Korzheva N, Mustaev A, Murakami K, Nair S, Goldfarb A, et al. Structural mechanism for rifampicin inhibition of bacterial RNA polymerase. Cell. 2001; 104 (6):901-912 - 64.
Wehrli W, Staehelin M. Actions of the rifamycins. Bacteriological Reviews. 1971; 35 (3):290-309 - 65.
Zumla A, Nahid P, Cole ST. Advances in the development of new tuberculosis drugs and treatment regimens. Nature Reviews Drug Discovery. 2013; 12 (5):388-404 - 66.
Boeree MJ, Diacon AH, Dawson R, Narunsky K, du Bois J, Venter A, et al. A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis. American Journal of Respiratory and Critical Care Medicine. 2015; 191 (9):1058-1065 - 67.
Jayaram R, Gaonkar S, Kaur P, Suresh BL, Mahesh BN, Jayashree R, et al. Pharmacokinetics-pharmacodynamics of rifampin in an aerosol infection model of tuberculosis. Antimicrobial Agents and Chemotherapy. 2003; 47 (7):2118-2124 - 68.
Rosenthal IM, Tasneen R, Peloquin CA, Zhang M, Almeida D, Mdluli KE, et al. Dose-ranging comparison of rifampin and rifapentine in two pathologically distinct murine models of tuberculosis. Antimicrobial Agents and Chemotherapy. 2012; 56 (8):4331-4340 - 69.
Koch A, Mizrahi V, Warner DF. The impact of drug resistance on Mycobacterium tuberculosis physiology: What can we learn from rifampicin? Emerging Microbes & Infections. 2014;3 (3):e17 - 70.
Jhingan GD, Kumari S, Jamwal SV, Kalam H, Arora D, Jain N, et al. Comparative proteomic analyses of avirulent, virulent, and clinical strains of Mycobacterium tuberculosis identify strain-specific patterns. Journal of Biological Chemistry. 2016;291 (27):14257-14273 - 71.
Portevin D, Sukumar S, Coscolla M, Shui G, Li B, Guan XL, et al. Lipidomics and genomics of Mycobacterium tuberculosis reveal lineage-specific trends in mycolic acid biosynthesis. Microbiologyopen. 2014;3 (6):823-835 - 72.
Nieto RL, Mehaffy C, Creissen E, Troudt J, Troy A, Bielefeldt-Ohmann H, et al. Virulence of Mycobacterium tuberculosis after acquisition of isoniazid resistance: Individual nature of katG mutants and the possible role of AhpC. PLoS One. 2016;11 (11):e0166807 - 73.
Chindelevitch L, Colijn C, Moodley P, Wilson D, Cohen T. ClassTR: Classifying within-host heterogeneity based on tandem repeats with application to Mycobacterium tuberculosis infections. PLoS Computational Biology. 2016;12 (2):e1004475 - 74.
Organization WH. Global Tuberculosis Report. 2016 - 75.
Bisson GP, Mehaffy C, Broeckling C, Prenni J, Rifat D, Lun DS, et al. Upregulation of the phthiocerol dimycocerosate biosynthetic pathway by rifampin-resistant, rpoB mutant Mycobacterium tuberculosis . Journal of Bacteriology. 2012;194 (23):6441-6452 - 76.
Kruh NA, Troudt J, Izzo A, Prenni J, Dobos KM. Portrait of a pathogen: The Mycobacterium tuberculosis proteome in vivo. PLoS One. 2010;5 (11):e13938 - 77.
Lucas MC, Wolfe LM, Hazenfield RM, Kurihara J, Kruh-Garcia NA, Belisle J, et al. Fractionation and analysis of mycobacterial proteins. Methods in Molecular Biology. 2015; 1285 :47-75 - 78.
Mehaffy C, Hess A, Prenni JE, Mathema B, Kreiswirth B, Dobos KM. Descriptive proteomic analysis shows protein variability between closely related clinical isolates of Mycobacterium tuberculosis . Proteomics. 2010;10 (10):1966-1984 - 79.
Mehaffy MC, Kruh-Garcia NA, Dobos KM. Prospective on Mycobacterium tuberculosis proteomics. Journal of Proteome Research. 2012;11 (1):17-25 - 80.
Nieto RL, Mehaffy C, Dobos KM. Comparing isogenic strains of Beijing genotype Mycobacterium tuberculosis after acquisition of Isoniazid resistance: A proteomics approach. Proteomics. 2016;16 (9):1376-1380 - 81.
Wolfe LM, Mahaffey SB, Kruh NA, Dobos KM. Proteomic definition of the cell wall of Mycobacterium tuberculosis . Journal of Proteome Research. 2010;9 (11):5816-5826 - 82.
Wolfe LM, Veeraraghavan U, Idicula-Thomas S, Schurer S, Wennerberg K, Reynolds R, et al. A chemical proteomics approach to profiling the ATP-binding proteome of Mycobacterium tuberculosis . Molecular and Cellular Proteomics. 2013;12 (6):1644-1660 - 83.
Aebersold R, Goodlett DR. Mass spectrometry in proteomics. Chemistry Review. 2001; 101 (2):269-295 - 84.
Zhang Y, Fonslow BR, Shan B, Baek MC, Yates JR, 3rd. Protein analysis by shotgun/bottom-up proteomics. Chemistry Review. 2013; 113 (4):2343-2394 - 85.
Hancock W, LaBaer J, Marko-Varga GA. Journal of Proteome Research - 10th Anniversary. Journal of Proteome Research. 2011; 10 (1):1-2 - 86.
Gengenbacher M, Mouritsen J, Schubert OT, Aebersold R, Kaufmann SH. Mycobacterium tuberculosis in the proteomics era. Microbiology Spectrum. 2014;2 (2) - 87.
Nogueira FC, Domont GB. Survey of shotgun proteomics. Methods in Molecular Biology. 2014; 1156 :3-23 - 88.
Heym B, Alzari PM, Honore N, Cole ST. Missense mutations in the catalase-peroxidase gene, katG, are associated with isoniazid resistance in Mycobacterium tuberculosis . Molecular Microbiology. 1995;15 (2):235-245 - 89.
Datta G, Nieto LM, Davidson RM, Mehaffy C, Pederson C, Dobos KM, et al. Longitudinal whole genome analysis of pre and post drug treatment Mycobacterium tuberculosis isolates reveals progressive steps to drug resistance. Tuberculosis (Edinburgh, Scotland). 2016;98 :50-55 - 90.
Richardson ET, Lin SY, Pinsky BA, Desmond E, Banaei N. First documentation of isoniazid reversion in Mycobacterium tuberculosis . The International Journal of Tuberculosis and Lung Disease. 2009;13 (11):1347-1354 - 91.
Jiang X, Zhang W, Gao F, Huang Y, Lv C, Wang H. Comparison of the proteome of isoniazid-resistant and -susceptible strains of Mycobacterium tuberculosis . Microbial Drug Resistance. 2006;12 (4):231-238 - 92.
Murphy H, Cashel M. Isolation of RNA polymerase suppressors of a (p)ppGpp deficiency. Methods in Enzymology. 2003; 371 :596-601 - 93.
Hu H, Zhang Q, Ochi K. Activation of antibiotic biosynthesis by specified mutations in the rpoB gene (encoding the RNA polymerase beta subunit) of Streptomyces lividans . Journal of Bacteriology. 2002;184 (14):3984-3991 - 94.
Inaoka T, Takahashi K, Yada H, Yoshida M, Ochi K. RNA polymerase mutation activates the production of a dormant antibiotic 3,3'-neotrehalosadiamine via an autoinduction mechanism in Bacillus subtilis . Journal of Biological Chemistry. 2004;279 (5):3885-3892 - 95.
Xu J, Tozawa Y, Lai C, Hayashi H, Ochi K. A rifampicin resistance mutation in the rpoB gene confers ppGpp-independent antibiotic production in Streptomyces coelicolor A3(2). Molecular Genetics & Genomics. 2002;268 (2):179-189 - 96.
Abadi FJ, Carter PE, Cash P, Pennington TH. Rifampin resistance in Neisseria meningitidis due to alterations in membrane permeability. Antimicrobial Agents and Chemotherapy. 1996;40 (3):646-651 - 97.
Cui L, Isii T, Fukuda M, Ochiai T, Neoh HM, Camargo IL, et al. An RpoB mutation confers dual heteroresistance to daptomycin and vancomycin in Staphylococcus aureus . Antimicrobial Agents and Chemotherapy. 2010;54 (12):5222-5233 - 98.
Watanabe Y, Cui L, Katayama Y, Kozue K, Hiramatsu K. Impact of rpoB mutations on reduced vancomycin susceptibility in Staphylococcus aureus . Journal of Clinical Microbiology. 2011;49 (7):2680-2684 - 99.
Louw GE, Warren RM, Gey van Pittius NC, Leon R, Jimenez A, Hernandez-Pando R, et al. Rifampicin reduces susceptibility to ofloxacin in rifampicin-resistant Mycobacterium tuberculosis through efflux. American Journal of Respiratory and Critical Care Medicine. 2011;184 (2):269-276 - 100.
Lahiri N, Shah RR, Layre E, Young D, Ford C, Murray MB, et al. Rifampin resistance mutations are associated with broad chemical remodeling of Mycobacterium tuberculosis . Journal of Biological Chemistry. 2016;291 (27):14248-14256 - 101.
Camacho LR, Constant P, Raynaud C, Laneelle MA, Triccas JA, Gicquel B, et al. Analysis of the phthiocerol dimycocerosate locus of Mycobacterium tuberculosis . Evidence that this lipid is involved in the cell wall permeability barrier. Journal of Biological Chemistry. 2001;276 (23):19845-19854 - 102.
Murry JP, Pandey AK, Sassetti CM, Rubin EJ. Phthiocerol dimycocerosate transport is required for resisting interferon-gamma-independent immunity. Journal of Infectious Diseases. 2009; 200 (5):774-782 - 103.
Singh A, Gopinath K, Sharma P, Bisht D, Sharma P, Singh N, et al. Comparative proteomic analysis of sequential isolates of Mycobacterium tuberculosis from a patient with pulmonary tuberculosis turning from drug sensitive to multidrug resistant. Indian Journal of Medical Research. 2015;141 (1):27-45 - 104.
Singhal N, Sharma P, Kumar M, Joshi B, Bisht D. Analysis of intracellular expressed proteins of Mycobacterium tuberculosis clinical isolates. Proteome Science. 2012;10 (1):14 - 105.
Truong PQ HD, Volker U, Hammer E. Using a label free quantitative proteomics approach to identify chnages in protein abundance in multidrug-resistant Mycobacterium tuberculosis . Indian Journal of Microbiology. 2015;55 (2):219-230 - 106.
Truong PQ HE, Salazar MG, Ha DTT, Huong NL, Hieu DM, Hoa NT, Thuy PT, Volker U. 2D DIGE proteomic analysis of multidrug resistant and susceptible clinical Mycobacterium tuberculosis isolates. Journal of Integrated OMICS. 2014;4 (1):28-36 - 107.
Yari S, Hadizadeh Tasbiti A, Ghanei M, Shokrgozar MA, Fateh A, Mahdian R, et al. Proteomic analysis of drug-resistant Mycobacterium tuberculosis by one-dimensional gel electrophoresis and charge chromatography. Archives of Microbiology. 2017;199 (1):9-15 - 108.
Layre E, Al-mubarak R, Belisle JT, Moody DB. Mycobacterial lipidomics. Microbiology Spectrum. 2014: 2 ;341-360 - 109.
Loots du T. An altered Mycobacterium tuberculosis metabolome induced by katG mutations resulting in isoniazid resistance. Antimicrobial Agents and Chemotherapy. 2014;58 (4):2144-2149