Journal of Biomedical Sciences

Keywords

Tuberculosis; Epidemiology; Drug resistance

Abbreviations

ATP: Adenosine Tri Phosphate; BCG: Bacillus Calmette-Guerin; HIV: Human Immunodeficiency Virus; MDR TB: Multi Drug-Resistant Tuberculosis; MoHFDRE: Ministry of Health Federal Democratic Republic of Ethiopia; MTB: Mycobacterium tuberculosis; RIF: Rifampicin; TB: Tuberculosis; WGS: Whole Genome Sequencing; WHO: World Health Organization

Introduction

Tuberculosis is a chronic infectious and zoonotic disease caused by the Mycobacterium tuberculosis complex. It is accountable for a lung infection (pulmonary tuberculosis) and other body parts (extrapulmonary tuberculosis). Antituberculosis drugs emerged since the 1940s and dramatically reduce mortality rates. In spite of highly efficacious treatment tuberculosis stay as a most public health constraint. Tuberculosis is ranked as the second cause of the mortality next to HIV infection. Tuberculosis declared as a global public health emergency since 1993 at a time of estimated 7-8 million cases and 1.3-1.6 million deaths occurred annually. In 2010 there were 8.8 million new cases of tuberculosis and 1.1 million deaths from tuberculosis among HIV negative and 0.35 million deaths from that HIV-associated tuberculosis and it is exacerbated due to the development of anti-tuberculosis drug resistance [1].

The emergence of resistance against anti-tuberculosis drug is the obstacle for the effectiveness of the treatment. Moreover, resistance to anti-tuberculosis drugs is a natural phenomenon occurring against Mycobacterium tuberculosis by the spontaneous chromosomal mutations. Inadequate tuberculosis treatment is accountable for the occurrence of drug-resistant Mycobacterium tuberculosis. Even single chromosomal mutations direct the resistance to two or more anti-tuberculosis drugs [2].

World health organization report of 2009 ranked Ethiopia seventh in the world and third in Africa for the burden of tuberculosis in 2008. In Ethiopia estimated incidence of 378 new cases per 100,000 persons, 163 new smear-positive cases per 100,000 persons and prevalence of 579 per 100,000 populations [3]. Ethiopia registered 146,172 cases of tuberculosis in the year of 2009/10. Among these new cases of 139,261; new smearpositive 46,132 (33.1%); new smear-negative 49,037 (35.2%) and extrapulmonary tuberculosis 44,092 (31.6%) [4]. This confirms that Ethiopia is endemic for the tuberculosis disease. According to drug resistance survey carried out in Ethiopia from 2003 to 2006 indicated that multidrug resistance tuberculosis is 11.8% in previously treated cases and 1.6% of newly diagnosed tuberculosis cases; include 5,200 cases annually [5].

Therefore, the objective of this paper is to review the status of anti-tuberculosis drug resistance.

Etiology and Routes of Transmission

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis complex. This complex includes M. tuberculosis (including subspecies M. canetti), M. bovis, M. bovis BCG, M. africanum, M. caprae, M. microti and M. pinnipedii [6]. Cough of a tuberculosis patient is a source of Mycobacterium tuberculosis and it disseminate to air during coughing. The persons who have inhaled air droplet and contact with TB patient become infected [7].

Epidemiology and Associated Factors of Tuberculosis

Tuberculosis is determined by the presence of poverty, malnutrition, overcrowding and incomplete health care system which are the predisposing factors [8]. In the latest time patients developing active tuberculosis is an estimated 9.6 million persons and 1.5 million deaths annually [8,9]. For instance, across the different countries the incidence of tuberculosis changes; in Western Europe 5 per 100,000 persons, whereas, 800 per 100,000 in South Africa [10]. According to the WHO, 5% of all new tuberculosis cases are due to multidrug-resistant tuberculosis. Moreover, MDR TB prevalence varies from region to regions. For example, MDR TB in eastern Europe and central Asia reaches up to 48% [9,11].

The two common pathways that lead to drug-resistant tuberculosis are acquired and primary drug resistance. Acquired drug resistance is resulted from inappropriate treatment, in the adequate or poor quality of drugs and inadequate drug intake in the presence of drug-susceptible tuberculosis. In the case of primary drug resistance direct exposure to the drug-resistant anti-tuberculosis. However, tuberculosis transmission or progression is prevented by various factors such as infection control and environmental interventions, good host immunity, latent tuberculosis treatment and high-quality diagnosis, treatment, patient support and management of drug-resistant tuberculosis [2,12]. While the increased transmission rate of drug-resistant tuberculosis aggravates the magnitude of tuberculosis burden [13].

Multidrug-resistant tuberculosis is resistant to isoniazid and rifampicin, but with or without resistance to other first-line drugs [14]. Extensive drug-resistant tuberculosis is resistant to isoniazid, rifampicin, and fluoroquinolones and any one of threesecond line injectables (kanamycin, amikacin, and capreomycin). It is reported in 2006 as a severe form of tuberculosis [14,15]. Totally drug-resistant tuberculosis is a resistance to all first and second-line anti-tuberculosis drugs and it is reported after one year of extensive drug-resistant described. However, total drug resistant tuberculosis definition still it is not recognized by the World Health Organization [14].

Extensively drug-resistant and totally drug-resistant tuberculosis developed as a consequence of failure to identify an appropriate treatment of multidrug-resistant tuberculosis patients [15,16]. The first case of totally drug-resistant tuberculosis reported in the USA from the patient who went to the USA to study English [17]. After that, it is reported in different places including Italy, Iran, India, and South Africa [18-21] Among the total cases of multidrug-resistant tuberculosis strains 10% are total drug-resistant tuberculosis [14].

Pathogenesis

Infection due to Mycobacterium tuberculosis could be an active or latent infection. Active infection is characterized by a wide range of granulomatous structures that includes bacterial laden, necrotic (caseating) lesions and central liquefaction, whereas latent infection is characterized by fibrotic and calcified lesions [22]. Mechanism of granulomatous lesions development is by the small and aerosolized particles of Mycobacterium tuberculosis reaches alveoli via inhalation then transported to tissue with the help of macrophages form aggregation with immune cells [23]. Disease development in immunocompromised and immunocompetent persons is different as consequences of immunocompromised persons develop poorly organized and noncaseating lesions, whilst immunocompetent persons produce a highly organized, caseating and cavitary lesions [24].

Drugs Used for Treatment of Tuberculosis and their Mechanism of Actions

Drugs used for the treatment tuberculosis classified as first and second line and new TB drugs based on their potency and safety issues.

First-line drugs

Isoniazid: Isoniazid commenced as an anti-tuberculosis drug since 1952 and act as a bactericidal and bacteriostatic for rapidly and slowly growing bacilli, respectively. It is also named as isonicotinic hydrazide and diffuses across Mycobacterium tuberculosis cell membrane [25]. The targets of isoniazid are KatG and inhA gene. KatG gene encodes two enzymes called catalase/peroxidase enzyme that activates prodrug and peroxynitrite involved in pathways of reactive nitrogen and oxygen intermediates [26,27]. InhA gene encodes NADHdependent enoyl-Acyl Carrier Protein (ACP)-reductase that inhibits mycolic acid synthesis [28,29].

Rifampicin: Rifampicin was isolated from Streptomyces mediterranei in 1957 from soil sample at Lepetit Research Laboratories of France and used as an anti-tuberculosis agent since 1972 [30]. It is still utilized as the best choice of antituberculosis drug. Rifampicin is lipophilic and diffuses across the cell membrane of Mycobacterium tuberculosis. The primarily targeted rpoB of DNA dependent-RNA polymerase β subunit and rpoB uses four ribonucleotide triphosphates as substrates to catalyze transcription of DNA into mRNA. Rifampicin binds to the β subunit of DNA dependent-RNA polymerase and inhibits transcription of mycobacteria [31-34].

Ethambutol: Ethambutol is active against growing bacilli because of its bacteriostatic nature and commenced as an antituberculosis drug since 1966. It hampers polymerization of cell wall component arabinogalactan and lipoarabinomannan and results in a buildup of intermediate arabinan biosynthesis Darabinofuranosyl- P-decaprenol and bacteriostatic effect [35,36]. Arabinosyl transferase enzyme is a target for the action of ethambutol in both Mycobacterium tuberculosis and Mycobacterium avium. The enzyme is encoded by the embCAB gene organized as an operon and engaged in the arabinogalactan synthesis [37,38].

Pyrazinamide: Pyrazinamide activity against Mycobacterium tuberculosis depends on the acidity and anaerobic conditions [32]. It is activated to pyrazines acid by enzyme pyrazinamide/ nicotinamidase that encoded by gene pncA [39]. Acidic condition favors the formation of protonated pyrazinoic acid that passes via a membrane and accumulated in the cell membrane of Mycobacterium tuberculosis which interrupts cell membrane potential and alters membrane transport [40]. RpsA gene encodes 30S ribosomal protein S1 responsible for the mRNA translation [41]. Gene panD participates in pantothenate biosynthesis by converting L-aspartate into beta-alanine [42]. Pyrazinamide new target, clpC1 (Rv3596c) that encode an ATP dependent ATPase is responsible for protein degradation by complex formation with protease clpP1 and clpP2 [43].

Streptomycin: Streptomycin isolated from the soil microorganism Streptomyces griseus in 1943 and the first antibiotic cure for tuberculosis [44,45]. It is active against growing bacilli, but not against non-growing or intracellular bacilli [46]. It targets both rpsl and rrs genes that encode 30S ribosomal protein S12 and 16S rRNA, respectively and finally inhibit the instigation of the translation in the protein synthesis [47,48].

Second-line drugs

Para-amino salicylic acid: There are two mechanisms of action for para-amino salicylic acid to produce the desired action. Firstly, inhibit folic acid synthesis by the action of dihydropteroate synthase and dihydrofolate synthase that generates hydroxyl dihydrofolate antimetabolite which inhibits dihydrofolate reductase enzyme responsible for the synthesis of folic acid [49]. Secondly, inhibit cell wall component mycobactin synthesis by reducing uptake of iron [32].

Ethionamide: Two genes play a role in the mechanism of actions ethionamide are ethA and inhA. EthA regulated by the transcriptional repressor ethR [50]. The mechanism of action of the ethionamide is a disruption of mycolic acid synthesis by which monooxygenase enzyme activated ethionamide that binds to NAD+ and forms an adduct which inhibits enoyl acyl- ACP reductase enzyme [51-54].

Cycloserine: Cycloserine is a product of the cyclic derivative of serine hydroxamic acid and terizidone and isolated from Streptomyces orchidaceous in the 1950s. Cycloserine mechanism of action is by interfering with mycobacterial cell wall synthesis through inhibition of L-alanine racemase enzyme encoded by alrA that produce D-alanine from L-alanine and D-phenylalanine synthetase enzyme indispensable for the formation of peptidoglycan and cell wall synthesis by incorporation of Dalanine into pentapeptide [55-57].

Fluoroquinolones: Fluoroquinolones discovered as a derivative of chloroquine antimalarial drug in the 1960s and used in human and veterinary medicine as a bactericidal agent [58]. Mechanism of action of the fluoroquinolones is primarily depended on the blocking of mycobacterial DNA replication by binding to α and β subunits of DNA gyrase (gyrA and gyrB), which catalyze the supercoiling of DNA and finally, inhibits DNA synthesis [59,60].

Aminoglycosides and polypeptides: This group includes aminoglycosides (kanamycin, amikacin) and polypeptides (capreomycin, viomyocin). The common features of these antibiotics are their mechanism of action inhibiting protein synthesis. Kanamycin and amikacin alter 16S rRNA and capreomycin and viomycin interfere with small and large subunits of the 70S ribosome [61-63].

Linezolid: Linezolid is a group of oxazolidinone that interrupt an early step in protein synthesis through binding to the assembly of the 23S ribosomal RNA of the 50S subunit. The gene rplC and rrl are involved in the mechanical action of Linezolid. The rplC gene possesses 654 bp in length that encodes 50S ribosomal L3 protein to contribute to the synthesis of the ribosomal peptidyltransferase. Hence, rrl gene possesses 3138 bp length that encodes 23S ribosomal RNA [64].

Newer TB drugs

Newer tuberculosis drugs emerged against MDR TB because of the discovery of the novel targets in the Mycobacterium tuberculosis.

Bedaquiline or TMC207: Bedaquiline is a member of diarylquinolines and bactericidal. ATP demanded by mycobacteria is generated by the atpE gene by encoding subunit C of the ATP synthase. Mechanism of action of the bedaquiniline involves blocking the proton pump of ATP synthase of Mycobacterium tuberculosis then depletes energy demand of both non replicating (dormant) and replicating mycobacteria and at the end result in cell death [65,66].

Delamanid or OPC 67683: Mycobacterial F420 coenzyme system component deazaflavin dependent nitroreductase and F420-dependent glucose 6-phosphate dehydrogenase enzyme are encoded by F420 coenzyme genes ddn and fgd1 gene, respectively [25,57]. Delamanid is a derivative of dihydronitroimidazooxazole and activated by deazaflavin dependent nitroreductase enzyme (Rv3547). Delamanid acts through interrupting the synthesis of the mycobacterial cell wall component. By means of radical intermediate produced during activation of delamanid between desnitroimidazooxazole derivative and delamanid inhibit the synthesis of methoxy-and keto-mycolic acid which is a crucial component of the mycobacterial cell wall. It is active against growing and nongrowing mycobacteria [67,68].

PA-824: PA-824 is a derivative of nitroimidazole and activated by deazaflavin dependent nitroreductase enzyme as that of delamanid. Mechanism action of PA-824 is not clear but could be described as its’ activity in replicating and non-replicating mycobacteria. In aerobically replicating mycobacterial cell PA-824 disrupts mycolic acid synthesis by the accumulation of hydroxymycolates instead of ketomycolates [67,69,70]. Accordingly, in hypoxic non replicating mycobacteria, PA-824 release Nitric oxide (NO) that interfere with cytochrome oxidase to disrupt energy metabolism of the cell wall [71,72].

SQ-109: SQ-109 is a synthetic analogous of ethambutol. The mechanism of action of the SQ-109 is not clear and has no inhibition activity against secreted Ag85 mycolyltransferase enzyme. Rather SQ-109 causes accumulation of trehalose monomycolate a precursor of trehalose dimycolate by hindering assembles of mycolic acids into the bacterial cell wall core. Mmpl3 is a target of SQ-109 and transporter of trehalose monomycolate of the mycobacteria [73].

Mechanism of Resistance to the Anti-Tuberculosis Drug

Different mechanisms of resistance to anti-tuberculosis drugs emerged because of the mycobacteria undergo several mutations to overcome harsh environmental conditions. Mutated genes are those responsible for the activation of anti- TB drugs and synthesis components of Mycobacteria cell structure.

First-line drugs

Isoniazid: Resistance to the isoniazid associated with the mutation of KatG and inhA gene. KatG gene mutant S315T cause multidrug resistance by reducing the ability of KatG gene that converts isoniazid to isonicotinic acid which is a precursor for the formation of INH-NAD adducts [74-76]. In addition, a new KatG gene mutant L101R changes hydrophobic leucine to hydrophilic arginine and result in conformational alteration of protein binding site and hinders bioactivation [77].

Mutations in different positions of inhA gene regulatory region includes -15C/T, -8T/C, -15/T and -17C/T related with resistance [57,77-79]. Recent studies reported that mutation of inhA regulatory region together with mutation of inhA coding region end up in high resistance to isoniazid and cross-resistance to ethionamide that structurally related to isoniazid [80]. In both resistant and susceptible strain to isoniazid, mutations reported were Rv0340-0343, fadE24, efpA and KasA that demand further studies on their resistance mechanism [81].

Rifampicin: Site responsible for the rifampicin resistance is a “ hot spot region ” of 81bp of rpoB called RIF-resistance determining the region (RRDR) that covers 507-533 codons and principally mutation in codons of 516, 526 and 531 [82,83]. Cross-resistance to rifabutin occurred at 532 codon mutation in the rpoB gene that changes serine to leucine [77,83,84]. Compulsatory mutation discovered in rpoA and rpoC which encodes α and β’ subunits of RNA polymerase, respectively [85]. The importance of these compulsatory mutations is for reinstating fitness and the emergence of multidrug-resistant strains [86].

Ethambutol: Ethambutol resistance is originated from a mutation of an embCAB operon that causes changes in the site of drug-protein binding [87]. Potential ethambutol resistance marker is the mutation of embB 306, but about 30% resistance is not related to embB gene mutation [88-90] About 70% of mutation in codons of 306, 406 or 497, 13% of mutation between codons 296 and 426, 15% mutations in the embedembA intergenic region and mutation of ubiA gene that encode for a decaprenylphosphoryl-5-phosphoribose (DPPR) synthase along with mutation in embB correlated with high resistance to ethambutol [91,92]. The Minimum Inhibitory Concentration (MIC) of ethambutol increases due to mutations in genes of embB, embC and genes involved in the biosynthesis and utilization pathway of the decaprenylphosphoryl-beta-Darabinose (DPA) called Rv3806C and Rv3792 [93,94].

Pyrazinamide: Pyrazinamide resistance is associated with mutations of pncA, rpsA, panD and clpP1 [95,96]. Hence, mutations of pncA gene is majorly responsible for the resistance that occurs especially at nucleotides of 359 and 374 and 82-262 bp regulatory regions, but no mutations detected at 561bp pncA gene [97,98]. Deletion of alanine at 438bp and overexpression of rpsA gene increases resistance to the Pyrazinamide [41].

Streptomycin: The primary cause of streptomycin resistance are mutations of rpsl, gidB and rrs [99,100] Mutation in rpsl is because of the replacement of lysine by arginine at positions 43 and 88 and in gidB conferring mutation to A80P gene product by targeting methylguanosine methyltransferase [100]. In rrs mostly mutations in the nucleotides 530 and 915 develop resistance and resistance to streptomycin is occurred commonly because of mutations in rpsl and rrs gene [101].

Second-line drugs

Para-amino salicylic acid: A mutation of Thr202Ala in thyA gene is related with resistance to para amino salicylic acid. In addition, mutation to folC gene is responsible for resistance.

Ethionamide: Mutations in the ethA or ethR and inhA or its promoter result in resistance to ethionamide and isoniazid [50]. High resistance against ethionamide and isoniazid is due to mutations in the inhA gene of -15C to -15T in the promoter region, S94A (Serine to alanine) and I94T (Isoleucine to threonine) [80].

Cycloserine: Cycloserine target in Mycobacterium tuberculosis is not well studied. However, alrA overexpression results in resistance [102].

Fluoroquinolones: Mutations of the gyrA and gyrB are responsible for the resistance to the fluoroquinolones. Resistance determining regions of gyrA and gyrB are 74-113 and 500-540 codons, respectively [103,104]. Mutations at different positions of gyrA Ala-74, Gly-88, Ala-90, Ser-91 and Asp-94 end in resistance [105]. Hence, Mutation to gyrB in clinical isolates is less common and being low resistant to fluoroquinolones [106].

But, synchronization of mutations of gyrA and gyrB, Ala543Val (gyrB)-Asp94Asn/Asp94Gly (gyrA) and Asn538lle (gyrB)- Asp94Ala (gyrA) leads to high resistance [107].

Aminoglycosides and polypeptides: It consists aminoglycosides (kanamycin and amikacin) and polypeptides (capreomycin and viomyocin). Mutation to rrs gene at the position of 1,400, 1401 and 1,483 bp associated with high level resistance to both kanamycin and amikacin [108,109]. Hence, the mutation of rrs gene at the codon A1401G is related to highlevel resistance to the kanamycin and amikacin as well as crossresistance to capreomycin. In addition, resistance to the capreomycin associated with mutation of C1402T or G1484T and result in cross-resistance to kanamycin and viomycin [110,111].

Linezolid: Resistance to the linezolid is due to the mutation of the target genes. The mutation T460C in rplC gene plays a great role in the resistance to the linezolid and mutations of G2576T and G2061T in rrl gene increases minimum inhibitory concentrations. However, mutations of these genes account only 29.4% of linezolid resistance to the Mycobacterium tuberculosis [112]. As a result, further study required to explore the resistance mechanisms of linezolid.

Newer TB drugs

Bedaquiline: Mutations of A63P and I66M of atpE gene associated with resistance to bedaquiline; mutations in Rv0678 and pepQ are observed in wild type population and it controls the significant mechanism of clinical resistance [113].

Delamanid: Mutations in ddn and fgd1 result in resistance to the Delamanid [114].

PA-824: The main way of resistance to the PA-824 are the nitroimidazole-oxazine specific protein that causes structural changes to the drug and mutations of fdg1 [70,114].

SQ-109: Mmpl3 gene mutation leads to the development of resistance to the SQ-109 [115]. Hence, the up-regulation of ahpc gene plays a role in the development of resistance against isoniazid, ethambutol, and SQ-109 [116].

Management of Anti-Tuberculosis Drug Resistance

Management of the multidrug-resistant tuberculosis is very complex because of drugs used are toxic and administered for a long period of time than susceptible tuberculosis accompanied with a lower likelihood of treatment success [117]. Therefore, the following things should be followed:

• Isoniazid and rifampicin drugs rapid susceptibility test: This assumption is to reduce the delay to start the correct secondline therapy and for the purpose to increase cure, decrease mortality, reduce additional drug resistance development and reduce the possibility of failure and relapse [118]. Gene Xpert MTB/ RIF is sufficient to start a second line tuberculosis regimen by the patient, but confirmation by the line probe assay is required due to the probability of the false-positive results

• Combinations of sputum smear microscopy and culture: This assumption is to indicate that only the smear microscope could lead to delayed detection of failure. Simultaneous use of sputum smear microscopy and culture test leads to differentiate patients bacteriologically positive or relapse back to positive after initially converted to negative [119]

• Drugs included in the treatment regimen of multidrugresistant tuberculosis are fluoroquinolones, later generation fluoroquinolones (levofloxacin, moxifloxacin) and ethionamide. In the treatment of multidrug-resistant tuberculosis four-second line anti-tuberculosis drugs expected to be effective and for the intensive phase pyrazinamide should be included. Treatment regimens of multidrug-resistant tuberculosis include at least pyrazinamide, fluoroquinolones, injectable or parenteral agent, ethionamide and either cycloserine or para-aminosalicylic acid should be included [119]

• In the treatment of the multi-drug resistant tuberculosis, an intensive phase requires at least 8 months duration and total treatment duration required at least 20 months for no previous multidrug-resistant tuberculosis treatment. The main purposes were to prevent death, the transmission of multidrug-resistant tuberculosis, avoid harms and minimize the use of resources. Following initiation of anti-tuberculosis treatment with in the first 8 weeks regardless/irrespective of CD4 cell count, antiretroviral therapy is given to all patients with the HIV and drug-resistant tuberculosis that demand second-line anti-tuberculosis drugs [119,120]

• In the extensively drug-resistant tuberculosis, the rate of cure is lower than multi drug-resistant tuberculosis. Otherwise, the principles of management are similar to the multi-drug resistant tuberculosis. The optimum number of drugs and duration of treatment are still uncertain. However, at least six groups for the intensive phase and four in the continuation phase with the highest treatment success. In addition, 6-9 months duration for the intensive phase and 20-25 months for the total duration of treatment required [119,120]

• New drugs such as bedaquiline and delamanid and new combination regimen enhance cure rate of extensively drugresistant tuberculosis. In addition, later generation of fluoroquinolones (moxifloxacin) also significantly improved treatment outcomes [121-127]

Conclusion and Future Prospects

Tuberculosis is a major disease that constrains public health. It is caused by Mycobacterium tuberculosis and effective antituberculosis drugs developed against TB. These drugs are classified as first and second line and new drugs based on their discovery time and effectiveness. However, drug resistance emerged because of bacteria undergoes revolution to escape harsh environment by chromosomal mutations.

Actively developing resistance and factors that propagate resistance development in the patient are still poorly understood and demands further explanation. Retrieval of mutation resistance in mycobacteria developed dynamically under antibiotic pressure for a long time. The relationship between drug resistance, fitness, and virulence of the organism requires further study.

The current rapid diagnostic gene Xpert MTB/RIF and line probe assays are limited in their ability to produce a comprehensive resistance profile. For this reason, rapid WGS is the most promising utility for the drug-resistant tuberculosis diagnosis. The main strategy to diminish drug resistance crisis is a personalized treatment that suggests the potential to improve treatment outcomes. It is by a means of limiting therapeutic regimen to efficacious drugs and then reduction of unnecessary pill burden and significantly reducing side effects of the current treatment.

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