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Molecular mechanism of drug resistance
First line drugs used in TB treatment
Second line drugs used in TB treatment
Drug resistance in Mycobacterium Tuberculosis
Author: Chan Tai Man
Tuberculosis (TB) has been one of the most serious public health problems in the world. Although many years of hard work by World Health Organization and different countries over the tuberculosis control programs, TB remains one of the top 10 causes of death worldwide (World Health Organization 2016a). The control programs are greatly hampered with the emergence of multidrug resistance tuberculosis (MDR-TB) and severe forms of drug resistance like extensively drug resistance tuberculosis (XDR-TB). In 2015, 10.4 million people were infected with tuberculosis while 1.8 million people were killed (World Health Organization 2016a). In this review, the drugs used to treat tuberculosis, which is classified into the first line and second line drugs, the mechanisms of drugs resistance and the diagnosis of tuberculosis will be discussed.
Tuberculosis is caused by bacteria Mycobacterium tuberculosis that is in the family Mycobacteriaceae (Ryan et al. 2004). It was first discovered by Robert Koch in 1882. M. tuberculosis has an unusual, waxy coating on its cell surface, which is attributed to the presence of mycolic acid. This makes the cells impervious to Gram staining. In clinical settings, it can be appeared in the form of Gram negative and Gram positive (Fu et al. 2000).
After the introduce of first anti-TB drug, streptomycin (STR), para-aminosalicylic acid (PAS), isoniazid (INH), drug resistance to these drugs were found in clinical isolates of M. tuberculosis (Crofton and Mitchison 1948). In order to cure the illness, physicians have to measure the drug resistance accurately and promptly. A critical proportion method was introduced by the Pasteur Institute in 1961 for drug susceptibility testing in TB. Eventually, this becomes a standard method for measuring drug resistance (Espinal 2003). Studies in various countries in the 1960s have shown that drug resistance in developing countries is higher than that of developed countries (Espinal 2003). After the usage of effective anti-TB drug rifampicin (RIF) in the 1960s and with the use of combination therapy, there was a drop in drug resistant and drug susceptible TB in the developed countries. This leads to a drop in interest and, as a result, funding in TB control programs. So, no concrete study of drug resistance on TB was performed and recorded for the following 20 years (Espinal 2003). In addition, HIV / AIDS in the 1980s led to an increase in TB transmission, which is also associated to outbreaks of multi drug resistant TB (MDR-TB), which is the resistant to RIF and INF (Edlin et al. 1992, Fischl et al. 1992).
Although TB is curable and preventable in most cases, a lack of control in TB management would lead to wide spread of TB and MDR-TB worldwide. Around 17% of the infected patients were killed in 2015 (World Health Organization 2016b). In 2015, there were an estimated number of 480,000 people (4.6% of total infected people) were suffered from multidrug-resistant TB (MDR-TB) (World Health Organization 2016b). With the high death rates assoiciated with MDR TB of around 50% to 80% and spans a relatively short time of around 4 to 16 weeks from diagnosis to death (Mathew et al. 2014). As a result, the Sustainable Development Goals (SDGs) and the End TB Strategy were introduced in 2015, which covers the period from 2016-2030 and 2016-2035 respectively (World Health Organization 2016b). Among all cases, the situation in the developing countries is invariably worse than the developed countries as high as 95% of the TB deaths occur in the low and middle income countries. 6 countries account for 60% of the cases in descending order: India, Indonesia, China, Nigeria, Pakistan and South Africa. In most cases, the TB drug resistance emerges when the anti-TB medicines are used inappropriately, incorrect prescription s given by health care providers, poor quality drugs and termination of treatments prematurely by patients from various reasons (World Health Organization 2016a).
Molecular mechanism of drug resistance
The mechanism of how M. tuberculosis develops drug resistances has to be investigated in order to better control the spreading of tuberculosis in the world. This also helps to prevent or control the development of drug resistance tuberculosis and to identify genes associated with drug resistance of new drugs (Johnson et al. 2006). Genetic and molecular analysis of M. tuberculosis suggests that accumulation of mutations in the drug target genes is the primarily contribution factor to drug resistance in M. tuberculosis. The mutations either lead to an altered target, for example, RNA polymerase and catalase-peroxidase in rifampicin and isoniazid resistance respectively, or a change in titration of the drug, like InhA inisoniazid resistance (Rattan et al. 1998). Resistance to anti-TB drugs can occur spontaneously with an estimated frequency of 3.5 x 10-6 for INH and 3.1 x 10-8 for RIF when there are mutations in the genome of M. tuberculosis (Johnson et al. 2006). As the chromosomal loci contributing to the resistance of different are not linked, the probability of drug resistance to both INH and RIF are usually extremely low, as the chance is the multiplication of the 2 independent frequencies, which is 9 x 10-14 (Dooley and Simone 1994). Apart from mutations of the genome of M. tuberculosis, the other occurrence of drug resistance is the acquired resistance. This arises when drug resistant mutants are selected as a result of ineffective treatment or patient non-compliance or as primary resistance when a patient is infected with a resistant strain (Johnson et al. 2006).
To effectively control the wide spread of TB across the world, (World Health Organization 2016b) has recently issued a new guidance in May 2016 that “all cases of rifampicin-resistant TB (RR-TB, with or without resistance to other drugs), including those with multidrug-resistant TB (MDR-TB), should be treated with a second-line MDR-TB treatment regimen. Globally in 2015, there were an estimated 480 000 new cases of MDR-TB and an additional 100 000 people with rifampicin-resistant TB who were also newly eligible for MDR-TB treatment.” Treatment can be divided into 2 categories of drugs: First line drugs and second line drugs.
First line drugs used in TB treatment
In the anti-TB regiment, the drugs should have an effective sterilizing activity which is effective in shortening the duration of the treatment. (Johnson et al. 2006). There are 4 first line drugs in treating TB are ethambutol (EMB), isoniazid (INH), pyrazinamide (PZA) and rifampicin (RMP) (Johnson et al. 2006). Rifampicin and isoniazid are considered to be the two most effective and powerful anti-TB drugs (World Health Organization 2016b). In most cases, a four-drug regiment is used for the TB treatment (Johnson et al. 2006).
Resistance to the first line anti-TB drugs are linked to the mutations of at least 10 genes: katG, inhA, ahpC, kasA and ndh for INH resistance; rpoB for RIF resistance, embB for EMB resistance, pncA for PZA resistance and rpsL and rrs for STR resistance (Johnson et al. 2006). The drug resistance for the 4 major first line drugs will be discussed below: INH, RIF, EMB and PZA. Isoniazid, or isonicotinic acid hydrazide (INH), was first synthesized in the early 19th century. However, the ability on treating TB was first known in 1951 (Barry Iii et al. 1998, Rattan et al. 1998, Slayden and Barry Iii 2000).
katG. INH enters the cell as a prodrug which is then converted by a catalase peroxidase encoded by katG. The peroxidase activity of the enzyme enables to activate INH to a toxic substance in the bacterial cell (D. Xu et al. 1996). The toxic substance then affects intracellular targets like mycolic acid biosynthesis which are an important component of the M. TB cell wall. The deterioration of mycolic acid synthesis gradually results in loss of cellular integrity and the bacteria are killed (Barry Iii et al. 1998). Middlebrook (1954) had demonstrated that a loss of catalase activity leads to INH resistance (Middlebrook 1954). The genetic studies found that transformation of INH-resistant Mycobacterium smegmatis and M. tuberculosis strains with a functional katG gene restored INH susceptibility and katG deletions give rise to INH resistance (Heym et al. 1999, Zhang et al. 1993, Zhang et al. 1992).
ahpC. Very often, a loss of katG activity due to the S315T amino acid substitution is accompanied by an increase in expression of ahpC, an alkyl hydroperoxide reductase protein which is capable of detoxifying damaging organic peroxides(Sherman et al. 1996). It was found that 5 different nucleotide alterations in the promoter region of the ahpC gene would lead to over expression of ahpC and subsequently INH resistance (Ramana Rao et al. 2011). The overexpression gives a detoxifying effect on organic peroxides within the cell and protects the bacteria against oxidative damage but not for INH. (Johnson et al. 2006).
inhA. The protein encoded by the inhA locus is one of the targets for activated INH. InhA is an enoyl-acyl carrier protein (ACP) reductase that is proposed to be the primary target for drug resistance to INH and one second line drug, ethionamide (ETH) (Banerjee et al. 1994). A ternary complex is formed when activated INH binds to the InhA -NADH complex that results in inhibition of mycolic acid biosynthesis. Six point mutations are associated with INH resistance within the structural inhA gene have been identified (Basso and Blanchard 1998, Ramaswamy et al. 2000).
kasA. There are considerable dispute on whether kasA is a possible target for INH resistance (Sherman et al. 1996). kasA encodes a â-ketoacyl-ACP synthase which is to synthesize mycolic acids. The mutations of this gene usually confer a low level of INH resistance. Genotypic analysis of the kasA gene shows 4 different amino acid substitutions involving codon 66 (GAT-AAT), codon 269 (GGT-AGT), codon 312 (GGC-AGC) and codon 413 (TTC-TTA) (Mdluli et al. 1998, Ramaswamy et al. 2000).
Ndh. Miesel et al. (1998) found a new INH resistance in M. semgmatis in 1998. The ndh gene encodes NADH dehydrogenase which is bound to the active site of inhA and a ternary complex with activated INH is formed. Structural studies have found that a reactive form of INH attacks the NAD(H) co-factor and a covalent INH-NAD adduct is generated. Mutations in the ndh gene lead to defects in the enzymatic activity. As a result, defects in the oxidation of NADH to NAD result in NADH accumulation and NAD depletion (Lee et al. 2001). The accumulation of NADH contributes to the inhibition of the binding effects of the INH-NAD adduct to the active site of the InhA enzyme (Miesel et al. 1998, Rozwarski et al. 1998). Rifampicin was introduced in 1972 as an anti-TB drug and together with INH are the two most effective first line drugs in short-course chemotherapy (Ramaswamy and Musser 1998, Ramaswamy et al. 2000). The action of RIF in combination with PZA shortens the routine TB treatment from 1 year to 6 months.
rpoB. The action of RIF is to interfere with transcription with the DNA-dependent RNA polymerase. It is composed of four different subunits (á, â, â’ and ó) which are encoded by rpoA, rpoB, rpoC and rpoD genes respectively. RIF kills the organism by binding to the â-subunit hindering transcription. A number of mutations and short deletions in the rpoB gene were identified by extensive studies on the gene in RIF resistant isolates of M. tuberculosis (Johnson et al. 2006). A number of 69 single nucleotide changes, 3 insertions, 16 deletion and 38 multiple nucleotide changes have been reported (Herrera et al. 2013). These changes were found in more than 70% of RIF resistant isolates (Herrera et al. 2013, Ramaswamy and Musser 1998, Ramaswamy et al. 2000). In addition, minimal inhibitory concentration showed mutations in coden 526 and 531 contributes to a high level of RIF resistance (Johnson et al. 2006).
Pyrazinamide (PZA) is a nicotinamide analog. The anti-TB activity was first discovered in 1952. PZA targets a fatty-acid synthesis enzyme and is in charge of killing persistent tubercle bacilli in the initial intensive phase of chemotherapy (Somoskovi et al. 2001). In addition, PZA has effective sterilizing activity that effectively shortens the chemotherapeutic regiment from 12 to 6 months. PZA, similar to INH, is a prodrug and is converted to the active form, pyrazinoic acid (POA) by the pyrazinamidase (PZase) encoded by pncA (Johnson et al. 2006). The activity of PZA is highly specific for M. tuberculosis only, while there is no effect on other mycobacteria (Johnson et al. 2006). PZA is only active in an acidic medium where POA accumulates in the cytoplasm due to an ineffective efflux pump. The accumulation results in a lowering of intracellular pH to a level that inactivates a vital fatty acid synthase (Zimhony et al. 2004). Cloning and characterization of the M. tuberculosis pncA gene showed that pncA mutations lead to PZA resistance (Scorpio and Zhang 1996). Different kinds of pncA mutations have been identified in more than 70% of PZA resistant clinical isolates scattered throughout the pncA gene (Scorpio et al. 1997, Scorpio and Zhang 1996, Sreevatsan et al. 1997a).
Ethambutol (EMB) is used in combination with other drugs when treating TB and is specific to the mycobacteria. EMB inhibits an arabinosyl transferase (embB) involved in cell wall iosynthesis (Takayama and Kilburn 1989). Studies by Telenti et al. found out 3 genes, designated embCAB, that encode homologous arabinosyl transferase enzymes involved in EMB resistance (Telenti et al. 1997). Further studies were performed and five mutations in codon 306 [(ATG-GTG), (ATG-CTG), (ATG-ATA), (ATG-ATC) and (ATG-ATT)] which result in three different amino acid substitutions (Val, Leu and Ile) in EMB-resistant isolates were found (Lee et al. 2002, Mokrousov et al. 2002, Sreevatsan et al. 1997b). These five mutations associated with a high rate of 70–90% of all EMB resistant isolates (Ramaswamy et al. 2000).
Second line drugs used in TB treatment
When treating the MDR-TB, which does not respond to the most powerful first line drug, isoniazid and rifampicin, second line drugs are used (World Health Organization 2016a). But the treatment options are limited and require extensive chemotherapy which usually takes up to 2 years of treatment and the medicines are also expensive and toxic (World Health Organization 2016a).
The following drugs are classified as second line drugs and will be discussed: aminoglycosides (kanamycin and amikacin) polypeptides (capreomycin, viomycin and enviomycin), fluoroquinolones (ofloxacin, ciprofloxacin, and gatifloxacin), D-cycloserine and thionamides (ethionamide and prothionamide) (World Health Organization 2001).
Ciproflaxin (CIP) and Ofloxacin (OFL) are the two fluoroquinolones (FQs) used in MDR-TB treatment (World Health Organization, 2001). The quinolones inactivate DNA gyrase, a type II DNA topoisomerase (Cynamon and Sklaney 2003, Ginsburg et al. 2003, Rattan et al. 1998). DNA gyrase is encoded by gyrA and gyrB (Takiff et al. 1994). The negative supercoils in closed circular DNA molecules are introduced (Ramaswamy and Musser 1998, Rattan et al. 1998). The quinolone resistance-determining region (QRDR) is a conserved region in the gyrA (320bp) and gyrB (375bp) genes (Ginsburg et al. 2003). These 2 genes are interaction points of FQ and gyrase (Ginsburg et al. 2003). Missense mutations in codon 90, 91, and 94 of gyrA gene are the main factors for resistance to FQs (Takiff et al. 1994, Chen Xu et al. 1996)
Kanamycin (KAN) and Aminokacin (AMI) are aminoglycosides that inhibit protein synthesis and so is not able to treat dormant M. tuberculosis (Johnson et al. 2006). Aminoglycosides function is to bind to bacterial ribosomes and disturb the elongation of the peptide chain in the bacteria (Johnson et al. 2006). Mutations in the rrs gene encoding for 16s rRNA are associated with drug resistance to KAN and AMI (Suzuki et al. 1998).
Ethionamide (ETH) is mechanistically and structurally similar to INH. ETH is also a prodrug activated by bacterial metabolism. The activated drug then has the ability to disrupt cell wall biosynthesis by inhibiting mycolic acid synthesis. Similar to INH, mutations in the promoter of the inhA gene are associated with drug resistance to ETH (Morlock et al. 2003).
D-Cycloserine (DCS), a cyclic analog of D-alanine, which is one of the central molecules of the cross linking step of peptidoglycan assembly (Cáceres et al. 1997, David 2001, Feng and Barletta 2003, Ramaswamy et al. 2000). DCS inhibits cell wall synthesis through competing with D-Alanine for two enzymes D-alanyl-D-alanine synthetase (Ddl) and D-alanine racemase (Alr) and inhibiting the synthesis of the enzymes proteins. An over expression of alr leads to drug resistance (Feng and Barletta 2003, Ramaswamy and Musser 1998).
Molecular methods are often used for the identification of mutations in resistance-causing genes provides a fast means to screen M. tuberculosis isolates for antibiotic resistance (Johnson et al. 2006). Mutation screening methods includes: DNA sequencing, probe based hybridization methods, PCR-RFLP, single-strand conformation polymorphism (SSCP), heteroduplex analysis (HA), molecular beacons and ARMS-PCR (Victor et al. 2002).
The use of the rapid test Xpert MTB/RIF® has expanded substantially since 2010, when WHO first recommended its use (World Health Organization 2016b). This method was developed by Cepheid, USA. The test simultaneously detects TB and resistance to rifampicin. Diagnosis can be made within 2 hours and is recommended by WHO as the initial diagnostic test in all persons with signs and symptoms of TB (World Health Organization 2016b). In 2015, more than 100 countries are using Xpert and 6.2 million cartridges were procured globally. In 2016, 4 new diagnostic tests were recommended by WHO – a rapid molecular test to detect TB at peripheral health centres where Xpert MTB/RIF cannot be used, and 3 tests, microscopy, WRDs (other than Xpert MTB/RIF), culture and drug susceptibility testing (DST), to detect resistance to first- and second-line TB medicines (World Health Organization 2016b)
In conclusion, tuberculosis threatens millions of lives per year on earth. Recently, the number of MDR-TB cases remains very high and as the death rate of MDR-TB is significantly higher than TB, the WHO has launched different TB campaigns. The molecular perspective mechanisms of how drug resistant is developed in first line and second line TB drugs are reviewed and the diagnoses methods used in 1990s and the recent diagnoses methods recommended by WHO are also discussed.
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- Quote paper
- Tai Man Chan (Author), 2016, Drug resistance in Mycobacterium Tuberculosis, Munich, GRIN Verlag, https://www.grin.com/document/347012