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ISSN: 2332-0877
Journal of Infectious Diseases & Therapy
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Isoniazid with Multiple Mode of Action on Various Mycobacterial Enzymes Resulting in Drug Resistance

Lingaraja Jena, Tapaswini Nayak, Shraddha Deshmukh, Gauri Wankhade, Pranita Waghmare and Bhaskar C Harinath*

Bioinformatics Centre, Biochemistry & JBTDRC, MGIMS, Sevagram, Maharashtra, India

*Corresponding Author:
Harinath BC
JB Tropical Disease Research Centre, Mahatma Gandhi Institute of Medical Sciences
Sevagram, 442 102 (Wardha) Maharashtra, India
Tel: 91-7152–284341-284355
Fax: (07152)-284038
E-mail: [email protected]

Received date: September 11, 2016; Accepted date: October 17, 2016; Published date: October 20, 2016

Citation: Jena L, Nayak T, Deshmukh S, Wankhade G, Waghmare P, et al. (2016) Isoniazid with Multiple Mode of Action on Various Mycobacterial Enzymes Resulting in Drug Resistance. J Infect Dis Ther 4:297. doi:10.4172/2332-0877.1000297

Copyright: © 2016 Jena L, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Isoniazid (INH), is one of the drugs shown to be effective and has been extensively used in TB control. Interestingly tuberculosis showed predominant drug resistance to isoniazid and thus lead to multi drug therapy in TB treatment. However, isoniazid is still advocated in latent TB and use as prophylactic in HIV infection and in children for prevention of TB. It is of interest that different studies revealing interaction of isoniazid with around 117 enzymes of mycobacteria influencing metabolic pathways by number of ways in addition to inhibiting mycolic acid synthesis and thus affecting growth of mycobacteria. The purpose of this review is to present the various mechanisms of action of isoniazid at different enzymes of MTB causing drug resistance.

Keywords

Tuberculosis; Isoniazid; Drug resistance; Mycobacterium; Metabolic pathway

Introduction

Tuberculosis (TB), being an oldest infectious disease, has been a major health problem worldwide. It is caused by Mycobacterium tuberculosis (MTB) which infects around one third of the world’s population. According to WHO Global Tuberculosis Report 2015, there were around 9.6 million people with active TB infection and amongst them 12% were HIV-positive. Further, in 2014 there were only 1,23,000 reported cases of multidrug-resistant TB (MDR-TB) amongst 4,80,000 cases [1]. The occurrences of extensively drug-resistant (XDR) tuberculosis have also been a rising risk in different regions around the globe [2]. The isoniazid (INH), also known as isonicotinyl hydrazine, one of the effective anti-TB drugs used for tuberculosis treatment is found to be resistant in different clinical strains of MTB [3]. Further, according to various studies, 82 different enzymes of mycobacteria associated with the interaction of INH, resulting in mutation and isoniazid drug resistance (Table 1) [4,5].

S/No Locus tag Name Protein Length Gene
name
PDB ID Mutation Pathway
1 Rv1772 hypothetical protein Rv1772 103 - - Thr4Ala  
2 Rv1909c ferric uptake regulation protein furA (furA) 150 furA - Ser5Pro  
3 Rv0340 hypothetical protein Rv0340 179 - - Val163Ile  
4 Rv2428 alkyl hydroperoxide reductase subunit C 195 ahpC 2BMX Inter-genic region
G(-46)A
 
5 Rv1483 3-oxoacyl-[acyl-carrier-protein] reductase 247 fabG1 1UZL Ala5Pro, Val14Leu, Thr21Ala Fatty acid biosynthesis
6 Rv1484 enoyl-(acyl carrier protein) reductase 269 inhA 1P44 Lys8Asn, Ile16Thr, Ile21Val/Thr,  Ile47Thr, Val78Ala, Ser94Ala/Leu, Ile95Pro, Ile95Thr, Ile194Thr, Arg202Gly, Glu217Asp,
promoter region
Fatty acid biosynthesis
7 Rv3566c arylamine n-acetyltransferase nat 283 nat 4BGF Gly67Arg, Gly207Glu • Nitrotoluene degradation
• Metabolic pathways
• Biosynthesis of secondary metabolites
8 Rv2243 acyl-carrier-protein S-malonyltransferase 302 fabD 2QC3 Ser275Asn • Fatty acid  biosynthesis
• Metabolic   pathways
• Fatty acid metabolism
9 Rv0129c secreted antigen 85-C FBPC (85C) 340 fbpC 4MQM Gly158Ser
-63(C/T), -23(A/C)
Glycerolipid metabolism
10 Rv2242 hypothetical protein Rv2242 414 - - Asp3Gly, Met323Thr  
11 Rv2245 3-oxoacyl-(acyl carrier protein) synthase II 416 kasA 4C6U Asp66Asn, Met77Ile, Arg121Lys, Gly269Ser, Gly312Ser, Gly387Asp, Phe413Leu Fatty acid biosynthesis
12 Rv1592c hypothetical protein Rv1592c 446 - - Pro42Leu, Val430Ala    
13 Rv1854c NADH dehydrogenase 463 ndh - Arg13Cys, Val18Ala, Thr110Ala, Leu239Pro, Arg268His Oxidative phosphorylation
14 Rv3139 acyl-CoA dehydrogenase FADE24 468 fadE24 - Insertion of  2 base pair (bp) at nucleotide position  -64  
15 Rv2247 acetyl/propionyl-CoA carboxylase beta subunit AccD6 473 accD6 4FB8 Asp229Gly • Fatty acid biosynthesis
• Valine, leucine  and isoleucine  degradation
• Pyruvate  Metabolism
• Glyoxylate and dicarboxylate metabolism
• Propanoate  Metabolism
• Carbon  Metabolism
• Fatty acid  metabolism
16 Rv0341 isoniazid inductible gene protein INIB 479 iniB - Deletion of  12 bp at nucleotide position 665  
17 Rv0343 isoniazid inductible gene protein INIC 493 iniC - Trp83Gly  
18 Rv2846c integral membrane efflux protein EfpA 530 efpA - Ile73Thr  
19 Rv0342 isoniazid inductible gene protein INIA 640 iniA - Pro3Ala, Arg537His  
20 Rv1908c catalase-peroxidase-peroxynitritase T KatG 740 katG 2CCA Ser315Thr, Ser315Asn, Arg463Leu, Ser17Asn, Gly19Asp, Ser140Asn/Arg, Gly279Asp, Gly285Asp, Gly316Asp,
Ser457Ile,
Gly593Asp
• Reactive  oxygen   species degradation
• superoxide radicals degradation
• Phenylalanine  metabolism
• Tryptophan  metabolism
• Metabolic  Pathways
• Biosynthesis of  secondary      metabolites
21 Rv3795 integral membrane indolylacetylinositol arabinosyltransferase EMBB 1098 embB - Tyr333His • Cell wall biosynthesis
• Mycolyl-arabinogalactan-peptidoglycan complex biosynthesis
22 Rv2427a Transcriptional regulator OxyR', pseudogene   oxyR' - -  
23 Rv0236c Alpha-(1>3)-arabino-furanosyltransferase 1,400 aftD - Thr797Ala Cell wall polysaccharide biosynthesis
24 Rv0932c Phosphate-binding protein 370   pstS2   Arg70Leu • ABC transporters,
• Two-component system
• Tuberculosis
25 Rv0985c Large-conductance mechano sensitive channel 151 mscL 2OAR Gly55Ala  
26 Rv0987 ABC transporter substrate-binding protein 855      - Ala819Pro  
27 Rv1877  MFS-type transporter 687     Val660Phe  
28 Rv2576c membrane protein 154       - Hia128Arg  
29 Rv2999 Peptidase M23B 321 lppY   Met313Thr  
30 Rv3382c 4-hydroxy-3-methylbut-2-enyl diphosphate reductase 2 329 ispH2   Gln178Arg • Terpenoid backbone   
biosynthesis • Metabolic   Pathways
• Biosynthesis  of secondary    
metabolites • Biosynthesis of antibiotics
31 Rv3448 ESX-4 secretion system protein 467 eccD4    - Ala193Pro  
32 Rv0194 Multidrug efflux ATP-binding/ permease protein 1194     Leu350Phe, Asp536His  
33 Rv0338c FeS-binding protein 882     Lys490Asn  
34 Rv0517 Possible membrane  acyltransferase 436     Ser408Gly  
35 Rv0793 Putative monooxygenase 101   1YOH Gly81Asp Antibiotic  biosynthesis
36 Rv0886 Probable ferredoxin / ferredoxin-NADP reductase 575 fprB   Ile413Phe • Metabolic  Pathway
• Photosynthesis
37 Rv1023 Enolase 429 eno   Ala348Ser • Glycolysis / Gluconeogenesis
• Methane  Metabolism
• Metabolic  Pathways
• Biosynthesis of  secondary
metabolites • Microbial Metabolism in
diverse environments •  Biosynthesis of Antibiotics
• Carbon metabolism,
• Biosynthesis of amino acids
• RNA degradation
38 Rv1355c molybdopterin biosynthesis protein 715 moeY   Ile710Val Molybdopterin biosynthesis
39 Rv1555 Fumarate reductase subunit D 125 frdD   Ile103Thr • Citrate cycle (TCA cycle)
• Oxidative  phosphorylation
• Pyruvate   Metabolism,
• Butanoate Metabolism,
• Metabolic Pathways
• Biosynthesis of  secondary    metabolites
• Microbial  metabolism in 
diverse environments • Biosynthesis of  Antibiotics
• Carbon Metabolism
40 Rv1850 Urease subunit alpha 577 ureC   Asp336Gly • Arginine  biosynthesis
• Purine  Metabolism
• Metabolic  Pathways
• Microbial metabolism   
     in diverse environments
41 Rv2967c Pyruvate carboxylase 1127 pca   Thr482Met • Citrate cycle (TCA cycle)
• Pyruvate metabolism
• Metabolic pathway
• Carbon metabolism
• Biosynthesis of amino acid
42 Rv3401 glycosyl  hydrolase 786     Leu114Pro Metabolic pathway
43 Rv3537 3-oxosteroid 1- dehydrogenase 563 kstD   Ala148pro • Steroid  Degradation
•  Metabolic  pathway
• Microbial  metabolic  in environments
44 Rv0574c Probable polyglutamine synthesis accessory protein 380        - Val16Ile Capsule biosynthesis
45 Rv1118c Conserved hypothetical protein 286     Gly30Cys  
46 Rv1504c Conserved hypothetical protein 199     Glu73Gly  
47 Rv1896c S-adenosyl-L-methionine-dependent methyltransferase 303     Lys132Glu Methylation
48 Rv1977 Conserved hypothetical protein 348     Ser2Pro  
49 Rv2184c hypothetical protein 379       Pro294Leu  
50 Rv2432c hypothetical protein 136       -   Tyr117His  
51 Rv2917 Alanine / arginine-rich protein 626     Thr95Ala Cell wall synthesis
52 Rv3181c Antitoxin protein 150 vapB49   Val39Gly  
53 Rv0131c acyl-CoA dehydrogenase 447 fadE1   Ala35Val • Fatty acid   Degradation
•  Valine, leucine ,isoleusine   degradation
• Beta alanine metabolism
•  Metabolic  Pathway
• Biosynthesis  of secondary metabolism
• Biosynthesis of  Antibiotic
• Carbon metabolism
• Fatty acid  Metabolism
• Propanoate Metabolism
54 Rv1527c Polyketide synthase 2,108 pks5   Gly2040Asp • Lipid  Biosynthesis
• Polyketide biosynthesis
55 Rv1729c S-adenosylmethionine-dependent methyltransferase 312     His238Arg Lipid metabolism                                              
56 Rv2383c phenyloxazoline synthase 1,414 mbtB   His1251Pro • Mycobactin  biosynthesis
• Siderophore biosynthesis
57 Rv2384 bifunctional salicyl-AMP ligase/salicyl-S-ArCP synthetase 565 mbtA   Gly18Ser • Polyketide  biosynthesis
• Mycobactin  biosynthesis
• Siderophore biosynthesis
58 Rv3392c Cyclopropane mycolic acid synthase 1 287 cmaA1 1KP9 Gln99Glu Mycolic  acid biosynthesis
59 Rv3480c diacyglycerol O-acyltransferase 497     Glu315Ala Triacylglycerol  biosynthesis
60 Rv3649 DEAD / DEAH box helicase domain containing protein 771     Asp459Gly Information pathway
61 Rv0355c PPE family protein 3.300 PPE8   Leu1213Pro lipid metabolism.
62 Rv2659c Prophage integrase 375     Val235Ala  
63 Rv1198 ESAT-6-like protein 94 esxL 4GZR Gln20Leu  
64 Rv1362c Mce-associated membrane Protein 220        - Asp95Ala  
65 Rv2869c Zinc metalloprotease 404 Rip1   Lys95Thr  
66 Rv2911 D-alanyl-D-alanine carboxy Peptidase 291 dacB2 4RYE Leu220Gln Peptidoglycan biosynthetic
67 Rv0086 Hydrogenase 488 hycQ   Ala322Val Metabolism  and respiration
68 Rv1844c 6-phosphogluconate dehydrogenase 485 gnd1   Ala400Thr • Pentose phosphate pathway
• Glutathione  Metabolism
• Metabolic  Pathways
• Biosynthesis  of secondary metabolites
• Microbial metabolism in
diverse environments • Biosynthesis of antibiotics
•  Carbon metabolism
69 Rv2296 Haloalkane dehalogenase 1 300 dhmA1   Ala211Val • Chlorocyclohexane and chlorobenzene degradation
• Chloroalkane and chloroalkene degradation
• Metabolic pathways
• Microbial metabolism in   diverse environments
70 Rv3299c Probable arylsulfatase 970 AtsB   Arg439Trp Sphingolipid  metabolism
71 Rv0104 Hypothetical protein 504     Ile13Leu Metabolic pathway
72 Rv1069c Conserved   hypothetical protein 587       - Val465Met  
73 Rv2955c Hypothetical protein 321       - Phe315Ile  
74 Rv0564c Glycerol-3-phosphate dehydrogenase 2 [NAD(P)+] 341 gpdA1 /gpsA   Pro131Ser • Glycerophospholipid metabolism
• Biosynthesis of secondary metabolites
•  CDP-diacylglycerol biosynthesis I
•  CDP- diacylglycerol biosynthesis II
75 Rv0726c S-adenosyl-L-methionine-
dependent methyltransferase
367     Leu258Pro Lipid metabolism                                             
76 Rv0667 DNA-directed RNA polymerase subunit beta 1,178 rpoB   Asp435Val •  Information  Pathways
•  Purine  Metabolism
•  Pyrimidine  Metabolism
• Metabolic pathway
• RNA polymerase
77 Rv1189 ECF RNA polymerase sigma factor 290 sigI   Arg76Cys Information pathway
78 Rv0578c PE-PGRS family protein 1,306 PE_PGRS7   Ala785Thr lipid metabolism
79 Rv1753c PPE family protein 1,053 ppe24   Thr669Ser lipid metabolism
80 Rv0094c Conserved hypothetical protein 317     Lys315Glu  
81 Rv1358 transcriptional regulatory protein 1159     TAG*1160Ser Cyclic  nucleotide
biosynthesis
82 Rv0175 Mce associated membrane protein 213     - Met138Thr  

Table 1: Mutations in MTB Genes / Proteins reported to be associated with Isoniazid resistance [4,5].

As INH has been used as a first-line drug in the prevention and treatment of TB [6], its mechanism of action has been studied for more than five decades. It is reported to produce various highly reactive compounds [7] which then target multiple enzymes of MTB [8]. Thus, the complex mode of action of isoniazid with number of enzymes needs study. Further, it is useful to understand how mutation in different MTB enzymes affects drug-enzyme interaction. This communication reviews the various mechanism of action of a single drug isoniazid at different MTB enzymes leading to drug resistance.

Mechanisms of Action of Isoniazid

Activation of INH by KatG and formation of INH-NAD(P) adduct

KatG of MTB encoded by Rv1908c has 740 amino acids in its protein sequence, is a multifunctional enzyme, showing both a catalase and a peroxynitritase activities [9,10]. Besides playing an important role in the intracellular survival of the pathogen within macrophages, it protects against reactive nitrogen and oxygen species produced by phagocytic cells [10]. Being a pro-drug, INH is activated by the catalase– peroxidase KatG and MnCl2 and forms isonicotinoyl radical or anion which then reacts with NAD+ and NADP+ [11], and subsequently generates INH-NAD(P) adducts [12]. Amongst these adducts, the INH-NAD reported to inhibit the enoyl-ACP reductase enzyme (InhA) whereas INH-NADP inhibit dfrA - encoded dihydrofolate reductase [13] and MabA (3-oxoacyl-ACP reductase) [14].

Inhibition of InhA by INH-NAD adduct

INH-NAD adduct was reported to inhibit InhA of MTB encoded by Rv1484 which is reported to block the synthesis of mycolic acid, a major lipid of the mycobacterial cell wall.

Our in silico docking study between InhA and truncated INH-NAD adduct, demonstrated that the adduct binds with InhA by forming a hydrogen bond with its substrate binding residue Tyr158 [15] which correlates the in vitro study by Nguyen et al. reporting that the INHNAD adduct as a potential inhibitor of InhA [16].

Truncated INH-NAD adduct

After profiling the MTB proteome using both the INH-NAD and INH-NADP adducts coupled to Sepharose solid supports, Argyrou et al. identified seventeen proteins (Table 2) that bind to these adducts with high affinity [13]. Further, the truncated form of INH–NAD adduct (4-isonicotinoylnicotinamide, 4-INN,) reported to have potential antimycobacterial activity [17]. The in silico docking study of truncated INH–NAD adducts with six MTB enzymes with known three-dimensional (3D) structure out of 17 proteins (Table 2), showed considerable binding affinity and thus revealing the truncated INH– NAD adducts as effective inhibitors for these proteins [15].

S/No Locus_tag Name Protein
Length
Locus PDB ID Pathway
1 Rv3248c S-adenosyl-L-homocysteine hydrolase 495 sahH 3DHY • Cysteine and methionine
• Metabolism
• Metabolic pathways
2 Rv0753c Methylmalonate-semialdehyde
dehydrogenase
510 mmsA   • Valine, leucine and isoleucine
• Degradation
• beta-Alanine metabolism.
• Inositol phosphate metabolism
• Propanoate metabolism
• Metabolic pathways
• Carbon metabolism
3 Rv1187 pyrroline-5-carboxylate dehydrogenase ROCA 543 rocA 4IHI • Alanine, aspartate and glutamate Metabolism
• Arginine and proline metabolism
• Metabolic pathways
4 Rv0155 NAD(P) transhydrogenase
subunit alpha
366 pntAa/ pntAA   • Nicotinate and nicotinamide metabolism
• Metabolic pathways
5 Rv2623 Universal stress protein 297 TB31.7 3CIS  
6 Rv1996 hypothetical protein 317      
7 Rv0468 3-hydroxybutyryl-CoA dehydrogenase 286 fadB2   • Phenylalanine metabolism
• Benzoate degradation
• Butanoate metabolism
• Metabolic pathways
• Microbial metabolism in diverse environments
8 Rv1484 enoyl-ACP reductase 269 inhA 1P44 • Fatty acid biosynthesis
• Metabolic pathways
9 Rv2691 TRK system potassium
uptake protein CEOB
227 ceoB / trkA    
10 Rv0091 bifunctional 5-methylthioadenosine nucleosidase / S-adenosylhomocysteine nucleosidase 255 Mtn / pfs   • Cysteine and methionine metabolism
• Metabolic pathways
• Biosynthesis of amino acids,
11 Rv2858c Aldehyde dehydrogenase 455 aldC   • Glycolysis / Gluconeogenesis
• Pentose and glucuronate interconversions
• Ascorbate and aldarate metabolism
• Fatty acid degradation
• Valine, leucine and isoleucine degradation
• Lysine degradation
• Arginine and proline metabolism
• Histidine metabolism
• Tryptophan metabolism
• beta-Alanine metabolism
• Glycerolipid metabolism
• Pyruvate metabolism
• Chloroalkane and chloroalkene degradation
• Limonene and pinene degradation
• Metabolic pathways
• Biosynthesis of secondary metabolites
• Microbial metabolism in diverse environments
• Biosynthesis of antibiotics
12 Rv1059 Hypothetical protein 354      
13 Rv3777 Oxidoreductase 328      
14 Rv2971 Oxidoreductase     4OTK  
15 Rv2766c 3-ketoacyl-ACP reductase 260      
16 Rv2671 Possible bifunctional enzyme riboflavin biosynthesis protein RibD 258 ribD   • Riboflavin metabolism
• Metabolic pathways
• Biosynthesis of secondary metabolites
17 Rv2763c Dihydrofolate reductase   (DHFR) 159 dfrA/ folA 4KL9 • One carbon pool by folate
• Folate biosynthesis
• Metabolic pathways
18 Rv1483 3-oxoacyl-ACP reductase 247 fabG1 /
mabA
1UZL • Fatty acid biosynthesis
• Biotin metabolism
• Biosynthesis of unsaturated fatty acids
• Metabolic pathways

Table 2: High Affinity INH-NAD (P) - binding proteins from Mycobacterium tuberculosis [13,14].

Acetylation of INH by NAT

The arylamine N-acetyltransferase (NAT) of MTB also reported to have direct interaction with INH like KatG. As a drug-metabolizing enzyme, NAT acetylates INH and forms INH to a therapeutically inactive form i.e. N-acetylate INH [18]. Payton et al. observed that the over expression of NAT leads to increased INH resistance in Mycobacterium smegmatis [19]. Further, when the gene was knockedout, the bacteria showed increased sensitivity to INH [19].

Isoniazid Drug Resistance

Mutation in different mycobacterial enzymes associated with INH resistance

The mechanism of INH resistance has been the focus of extensive study. It is broadly reported that INH resistance in MTB has been associated with mutations in different genes [7] such as katG, inhA, kasA, ahpC etc. Mutation in NADH dehydrogenase, encoded by ndh also reported to be linked with INH resistance [20]. Further, mutation in promoter region of inhA strongly linked with extensively drugresistant tuberculosis [21].

Besides 22 genes of MTB reported in Tuberculosis Drug Resistance Mutation Database, which were associated with INH resistance [4], Shekar et al. identified 60 novel genes associated with INH resistance in INH-resistant clinical isolates of MTB by their whole genome sequencing [5]. Most of the genes are associated with important metabolic pathways of MTB such as biosynthesis of secondary metabolites, antibiotics, amino acid, fatty acid; carbon metabolism; cell wall biosynthesis; glycolysis/gluconeogenesis, glutathione metabolism, glyoxylate and dicarboxylate metabolism, lipid biosynthesis, lipid metabolism, metabolic pathway, microbial metabolism in diverse environments, mycolic acid, nitrotoluene degradation, oxidative phosphorylation etc [22,23].

As KatG is associated with activation of INH, mutation in its gene plays an important role in INH resistance. Among various mutations identified in KatG, mutation at S315T and S315N has been widely reported in INH resistance strains. Our computational studies also showed that KatG mutations (S315T/S315N) prevent free radical formation that leads to drug resistance [24].

Two mutations in NAT enzymes (G207E and G67R), reported in MTB clinical isolates associated with INH resistance. From the molecular dynamics (MD) simulation analysis of NAT wild type and mutants (G67R and G207E) models, it was observed that these mutations increases the stability of the binding interfaces of enzyme by providing extra electrostatic interaction with neighboring amino acids. This stability might facilitate in rapid acetylation of INH and detoxification and leads to isoniazid resistance [25].

The mycobacterial NADH pyrophosphatase (NudC) reported to have an important role in the degradation of INH-NAD adduct (the active forms of isoniazid) and ETH-NAD adduct (active form of ethionamide (ETH)) that leads to INH and ETH inactivation. The polymorphism P237Q leads to loss of enzymatic activity and thus leads to INH and ETH resistance [26,27]. Further, a silent mutation in mabA (Rv1483), at nucleotide position 609 (g609a), leads to INH resistance in MTB [28].

Mycothiol (MSH), a major low molecular mass thiol in mycobacteria has antioxidant activity as well as the ability to detoxify a variety of toxic compounds. Four genes such as mshA (Rv0486), mshB (Rv1170), mshC (Rv2130c) and mshD (Rv0819) involves in Mycothiol biosynthesis. Buchmeier et al. observed that the MTB mutant (613 bp deletion within the mshB gene) showing increase resistance to Isoniazid [29]. Further, the mshA (Rv0486) gene of MTB encoding glycosyltransferase involved in the first step of mycothiol biosynthesis [10]. Jagielski et al. observed that a defective mshA gene (frame shift mutation - insC1283) might contribute to the increase in isoniazid resistance [30].

Other Enzymes Associated with INH Resistance

The MTB glf (Rv3809c) gene encoding UDP-galactopyranose mutase, catalyzes the conversion of UDP-galactopyranose into UDPgalactofuranose through a 2-keto intermediate. It was reported that the over expression of Glf enzyme bound with the modified form of INH or by sequestering a factor such as NAD+ required for INH activity and thus might contribute to INH resistance [31]. Further, Pasca et al. observed that over expression of transmembrane transport protein MmpL7 encoded by mmpL7 (Rv2942) gene, in Mycobacterium smegmatis leads to high level INH resistance [32]. Yang et al. observed that InbR, a transcriptional regulatory protein which is encoded by Rv0275c, directly bind with INH and involved in isoniazid resistance [33]. Pandey et al. observed the over expression of Rv1475c (acn) gene, encoding Aconitate hydratase-A enzyme in clinical isolate of MTB resistant to rifampicin, isoniazid, ethambutol and kanamcyin [34] which suggested that Rv1475c might have some important role in INH resistance [35].

Though INH resistance is mostly due to the chromosomal mutations in the target genes, around 20-30% of INH resistant MTB isolates do not have mutations in any of the genes linked with resistance to INH [36] which suggests that other mechanism(s), namely efflux pump systems of MTB may be involved in INH resistance. The over expression of efflux pump genes such as efpA, mmpL7, mmr, p55 and the Tap-like gene Rv1258c etc are shown to contribute for INH resistance [36]. Further, efpA, jefA (Rv2459), drrA, drrB, mmr, Rv1250, Rv1634 and Rv0849 were reported to be over expressed under isoniazid or rifampicin stress [37]. Besides some other genes of MTB (Table 3) of an INH-sensitive strain, are also observed to be induced by isoniazid or ethionamide treatment [38].

S/No Locus_tag Name Protein
Length
Locus PDB ID Pathway
1 Rv2243 Malonyl CoA-acyl carrier protein transacylase 302 FabD 2QC3 • Fatty acid biosynthesis
• Lipid metabolism
2 Rv2244 Meromycolate extension  acyl carrier protein 115 acpM 1KLP  
3 Rv2245 3-oxoacyl-[acyl-carrier-protein] synthase 1 416 kasA 4C6U • Fatty acid biosynthesis
• Lipid metabolism
 
4 Rv2246 3-oxoacyl-[acyl-carrier-protein] synthase 2 417 kasB   fatty acid biosynthesis
Lipid metabolism
5 Rv2247 Propionyl-CoA carboxylase beta chain 6 473 AccD6 4FB8 • Fatty acid biosynthesis
• Valine, leucine and isoleucine degradation
• Pyruvate metabolism
• Glyoxylate and dicarboxylate metabolism
• Propanoate metabolism
• Metabolic pathways
• Biosynthesis of secondary metabolites
• Microbial metabolism in diverse environments
• Biosynthesis of antibiotics
• Carbon metabolism
• Fatty acid metabolism
6 Rv0129c Diacylglycerol acyltransferase/mycolyl-transferase Ag85C 340 fbpC 4MQM • Glycerolipid metabolism
• Metabolic pathways
 
7 Rv3140 Acyl-CoA dehydrogenase 401 FadE23   • Fatty acid degradation
• Valine, leucine and isoleucine degradation
• Beta-Alanine metabolism
• Propanoate metabolism
• Metabolic pathways
• Biosynthesis of secondary metabolites
• Biosynthesis of antibiotics
• Carbon metabolism
• Fatty acid metabolism
8 Rv3139 Butyryl-CoA dehydrogenase 468 FadE24    
9 Rv2428 Alkyl hydroperoxide reductase subunit C 195 ahpc 2BMX • Glutathione metabolism
• Metabolic pathways
10 Rv2846c MFS-type transporter EfpA 530 efpA    
11 Rv1592c Probable inactive lipase 446      
12 Rv1772 Hypothetical protein 103      
13 Rv0341 Isoniazid-induced protein 479  iniB    
14 Rv0342 Isoniazid-induced protein 640 iniA    
15 Rv0343 Isoniazid-induced protein 493 iniC    

Table 3: Genes induces by INH or ethionamide treatment of an INH-sensitive strain [38].

Though, the in depth molecular mechanism of INH resistance in number of mycobacterial proteins from drug resistance strains is yet to be thoroughly understood, many studies proposed the association of INH with number of MTB proteins in different ways such as direct activation by KatG, acetylation by NAT, inhibiting different enzymes through adduct formation, inducing different enzymes etc. Further, mutations in many enzymes of MTB are reported to be associated with INH resistances which are supposed to associate with different important metabolic pathways of MTB. The consequence of mutation of those enzymes on respective pathways needs further study so as to reveal other mechanisms of INH resistance.

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