Drug resistant Tuberculosis: A review

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Highlights

  • •

    Inappropriate treatment of Tuberculosis leads to MDR-TB and finally TDR-TB.

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    Several genetic changes in M. tuberculosis lead to insensitivity to anti-TB drugs.

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    Mutation in rpoB gene of the bacterium causes resistance to rifampicin.

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    Resistance to fluroquilonone gives rise to XDR-TB strain.

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    TDR-TB is resistant to all first and second line drugs as well as to new drugs.

Abstract

Tuberculosis (TB) was announced as a global emergency in 1993. There was an alarming counter attack of TB worldwide. However, when it was known that TB can be cured completely, the general public became ignorant towards the infection. The pathogenic organism Mycobacterium tuberculosis continuously evolved to resist the antagonist drugs. This has led to the outbreak of resistant strain that gave rise to “Multi Drug Resistant-Tuberculosis” and “Extensively Drug Resistant Tuberculosis” that can still be cured with a lower success rate. While the mechanism of resistance proceeds further, it ultimately causes unmanageable totally drug resistant TB (TDR-TB). Studying the molecular mechanisms underlying the resistance to drugs would help us grasp the genetics and pathophysiology of the disease. In this review, we present the molecular mechanisms behind Mycobacterium tolerance to drugs and their approach towards the development of multi-drug resistant, extremely drug resistant and totally drug resistant TB.

Introduction

Tuberculosis (TB) is one of the epidemics that highly threatened the global public health. It is a lethal airborne infection caused by Mycobacterium tuberculosis. TB is a deadly disease of mankind since ancient times, and it has always caused a threat to public health leading to morbidity and mortality. The global outbreak of Tuberculosis in 1993 led the “World Health Organization” to announce TB as a matter of high-priority [1,2]. In the year 2017, World Health Organization (WHO) had estimated around 10 million people to be infected by the disease and about 6.4 million individuals were newly diagnosed with TB. It was further reported that around 1.3 million patients succumbed almost every year due to Tuberculosis [3]. Treatment of TB is even more difficult and challenging with the emergence of drug-resistant variants of Mycobacterium tuberculosis. In 2012, about 45,000 cases of MDR-TB were identified and an estimated 170,000 casualties occurred because of TB. The condition of MDR-TB becomes worse when Mycobacterium strain gains resistance to more drugs [4]. Emergence of resistance strains to commonly used anti-TB drugs has caused dilemma to researchers. Among all the infectious diseases, tuberculosis reports the highest death rate worldwide exceeding HIV/AIDS [5]. Mycobacterium genome possessing mutation and other structural changes can evade the drugs commonly used to inhibit them. The outbreak of resistance made the control measures and medication of the disease more complicated, especially when the patient is co-infected with HIV virus [6]. The appearance and progression of the resistant strain of Mycobacterium tuberculosis depends largely on the genetic mutant selection [7]. The Mycobacterium population takes advantage of the arising mutants under selective pressure and makes themselves survive by choosing antibiotic resistance as the predominant trait [8]. Both genetic and phenotypic resistances are the two basic types that are widely found. Chromosomal gene mutation also leads to changes in the bacteria at the genetic level that develops drug resistance [9]. Virulence of the Mycobacterium, genetic factors of the host, HIV infection and incomplete treatment of the patient altogether contribute to the outbreak of drug resistant TB [10]. Mycobacterium resistant strain develops because of mutation which occurs sequentially [11]. Drug resistance in Mycobacterium is established by single nucleotide polymorphisms, chromosomal gene rearrangement encoding the drug target, the prodrugs metabolized by the enzymes to their active forms [12]. Mutation can also cause drug resistance by decreasing the accumulation of the drug in the bacterium or inactivation of the drugs. The ability of the drugs to bind to the target genes may be decreased by mutation. When the expressions of the target genes are increased by mutation to the extent that the drugs are no longer capable to inhibit the target, then also resistance can develop in the bacterium [13]. This review highlights the molecular mechanisms of drug resistance in Mycobacterium tuberculosis for gaining more information in understanding the resistance of anti-TB drugs for effective control and TB management in order to combat the ailment.

Section snippets

Initial phase

When an active TB patient coughs or sneezes releasing into the air a droplet of TB germ, it is often inhaled by others in the surrounding then the transmission of TB begins [14]. Tubercle bacilli travel along the aveolar passage and reach the lung. Once in the host macrophages, the tubercle bacilli confront the hostile environment of the macrophages. The normal mode of phagosome maturation cycle, which is characterized by the fusion of phagosome and lysosomes, results in the release of a

Types of resistance to drugs

Both genetic and phenotypic resistance are the two basic types of resistance widely found [9]. The primary mechanism of drug resistance by Mycobacterium tuberculosis can be summarized under intrinsic and acquired resistance.

Rifampicin

This drug has been extensively used in the treatment of problems related to bacteria, which play the key role behind the fighting of tuberculosis since 1972 [29]. It has been considered to be most effective and efficiently used as the first line anti-TB drugs which are exclusively active against growing and non-growing bacilli of the Mycobacterium tuberculosis [30]. This group of antibiotics is known to be isolated solely from Streptomyces mediterranei [31]. The use of rifampicin has shortened

Resistance to both first and second line drugs and emergence of extensively drug resistant TB (XDR-TB)

In March 2005, the center for disease control and prevention (CDC) first introduced the term extensively drug resistant TB (XDR-TB) [86]. XDR-TB may be defined as insensitivity to fluoroquinolones such as levofloxacin and moxifloxacin, and any of the 2nd line injectable drugs amikacin, kanamycin and also capreomycin in addition to resistance to the first line drugs isoniazid and rifampicin [87]. Extensively drug resistant TB occurs as a consequence of mishandling the MDR-TB patients [88]. By

Bedaquiline

This drug acts by degrading the cell membrane of the Mycobacterium and interferes with ATP synthase encoded by AtpE gene. Bedaquiline attaches to ATP synthase at its subunit C [36]. Bedaquiline belongs to the class diarylquinolines and is also referred as TMC207 or R207910 [99]. It is effective against both growing and non-growing bacilli [100]. However, resistance to Bedaquiline develops because of the occurrence of mutation in the AtpE gene (A63 P,166 M) that codes for the subunit C of the Fo

The untreatable total drug resistance (TDR-TB)

Mycobacterium tuberculosis strain that possesses resistance to all first line drugs (Isoniazid, rifampicin, streptomyces, pyrazinamide, ethambutol) (Fig. 1) and second line drugs (Ethionamide, para amino salicylic acid, cycloserine, ofloxacin, amikacin, ciprofloxacin, capreomycin and kanamycin) (Fig. 2) are referred to as totally drug resistant [108]. TDR-TB isolates show certain variation morphologically when determined at the cellular and molecular level [109]. Employing transmission

Diagnosis of tuberculosis

The diagnosis of tuberculosis can be initiated by investigating the medical history of the patient. Before giving any preventive treatment, patients with active TB should be screened for symptoms [112]. Examination of the physical condition of the patient is to be followed by test for infection by the bacterium [113]. Resistance to drug can also be tested by isolating the tubercle bacilli and performing the drug susceptibility testing (DST) [114]. Diagnosis of drug resistant TB is also done by

Treatment for Tuberculosis

Standardized administration and appropriate treatment of persons with Tuberculosis are highly essential for lowering the increased rate of tuberculosis which is threatening global public health [123]. For the first two months patients are given the first line drugs (isoniazid, rifampicin, parazinamide, ethambutol) followed by another additional period of 4–6 months with rifampicin and isoniazid to be fully cured. According to WHO, daily treatment must be offered to person diagnosed with

Prevention of Tuberculosis

Prevention of tuberculosis infection involves a set of control measures [91]. Vaccination is one of the preventive efforts. Children are immunized with BCG vaccine to protect from the disease and is known to cause a 30 % decrease in the infection rate [130]. Another preventative measure for drug resistance is by helping the patient to understand the consequences of resistant TB and making a time table for the drugs to be taken [131]. Transmission of drug resistance can be prevented by

Conclusion

Tuberculosis remains a deadly disease in spite of the stern measures taken towards its treatment. The main reasons behind its prevalence are the low economic status, societal negligence, poor resources, incomplete treatment etc. Tuberculosis is curable until the outbreak of the totally drug resistant type which is unresponsive to all available drugs. Although the success rate is low in XDR-TB and MDR-TB cases, yet with proper management, healing is still possible. Careful management of

Author credit statement

JLK, DN and SC decided the subject of the review. The review article, figure and table were prepared by JLK and DN under the guidance of SC. Further, SC supervised the entire work, reviewed and edited the final manuscript. JLK, DN and SC read and approved the final manuscript for publication.

Funding

Unfunded.

Ethical clearance

Not applicable.

Declaration of Competing Interest

None.

Acknowledgement

We are thankful to Assam University, Silchar, Assam, India for providing the necessary facilities in carrying out this work.

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