Pathogenesis of Mycobacterium Tuberculosis, mode of action ...

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Sikandar et al., (2021) Pathogenesis of Mycobacterium Tuberculosis, mode of action of drugs and advancement in anti-

tuberculosis drug development: A Comprehensive review. Innt. Med.

Health Sci. 1(1):40-55. Uoi: 40-55-01(1)2021MHS21-107-BR21-

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Pathogenesis of Mycobacterium Tuberculosis, mode of action of drugs and advancement in anti-tuberculosis drug development: A Comprehensive review Muhammad Sikandar1*, Abdul Samad Munir2, Abu Bakar Siddique1, Muhammad Bilal3, Sana Aftab6, Sidra Sulehri7, Muhammad Arif Ali4, Rimsha Batool5, Mehwish Aslam1 1Department of Zoology Wildlife and Fisheries, University of Agriculture, Faisalabad, Punjab, Pakistan 2Department of Chemistry, Government College University Faisalabad, Punjab, Pakistan 3Department of Microbiology, Government College University, Faisalabad, Punjab, Pakistan 4Department of Physiotherapy, Government College University Faisalabad, Punjab, Pakistan 5Department of Biosciences, University of Wah, Punjab, Rawalpindi, Pakistan. 6Department of Pediatric Medicine Pakistan Institute of Medical Sciences, Islamabad 7Department of Pharmacy, Comsats University Islamabad, Pakistan *Corresponding Author: [email protected] Tuberculosis (TB) is the 9th main cause of death worldwide, outnumbering all other infectious diseases. With rising treatment resistance, the epidemic persists, necessitating a great deal of attention and investment if the disease is to be eradicated. Due to the lack of progress in susceptible TB therapy over the previous four decades and the emergence of medication resistance, new treatments and regimens are necessary. Despite the relatively low number of money devoted, recent progress with major advancements has been made through improved collaboration and research networks. The novel medications bed aquiline and delamanid, as well as reallocation pharmaceuticals linezolid, clofazimine, and carbapenems, are increasingly being employed in drug-resistant TB regimens. However, this standardization ignores individual differences in infection susceptibility, immunological response, drug pharmacokinetics, and the length of treatment required to achieve relapse-free cure. The current review contains information on anti-tuberculosis medications that have been utilized in the last decade, as well as the role of precision medicine in combating drug resistance. Keywords: Mycobacterium Tuberculosis, pharmaceuticals, drugs, resistance

INTRODUCTION Tuberculosis (TB) is caused by a bacterium Mycobacterium tuberculosis (Mtb). Previously only affecting the poor, tuberculosis is now recognized as a hazard to the entire population (Cholo et al 2014). Globally tuberculosis (TB) is the main cause of death related to infections. In 2014, 9 million individuals were affected by tuberculosis (TB) and 1.5 million people were dead due to TB, with about half million of them being HIV positive (Bradley et al 2015). The spread of multidrug-resistant Mtb strains has aggravated the problem. Tuberculosis is referred as MDR-TB that has developed resistance to at least two of the most effective first-line anti-TB medications, isoniazid and rifampicin (Mitchison et al 2005). Extensively drug-resistant tuberculosis (XDR-TB) is a kind of MDR-TB in which the disease causing TB strain is also immune to a fluoroquinolone and at least one of the three second-line injectable anti-TB drugs. Each year, around half million cases of MDR-TB cases are diagnosed around the world (Dey et al 2014). In newly diagnosed instances, the incidence is 3.3 percent, while previously treated cases have a 20 percent incidence. Furthermore, the therapeutic success rate is only 50%. Despite the global average of 3.3 percent for MDR-TB incidence in new TB cases, in some high-incidence settings (e.g. former Soviet Union countries), not less than 20% to 30% of new cases are MDR develop XDR-TB (Gardner et al 2005). Treatment of active, drug-resistant tuberculosis should be shortened and simplified. Improve the efficacy and safety of drug-resistant illness treatment while also reducing the length of time patients are on it.

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Sikandar et al. Pathogenesis of Mycobacterium Tuberculosis

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Develop medications that can be easily Co-

administered with ARVs for people who have TB and are also HIV positive. Reduce the time it takes to treat latent tuberculosis (Albanna et al 2013). During the last few years, the search for new anti-TB medications has gotten a lot of attention. Several options are being studied, and the present portfolio of promising chemicals includes an intriguing number of compounds.

Screening libraries of chemical compounds and natural products for new anti-TB medications, as well as identifying possible microorganism targets and designing new molecules, are all part of the strategy (Walker et al 2015).

Mechanism of Disease Progression Macrophages, dendritic cells, and T cells in

combination in most people with LTBI is enough to keep the infection under control and asymptomatic. However, infection can progress to clinical disease in a subset of hosts in as little as weeks or as long as decades for unexplained causes. Some natural human immunology investigations have offered information on why some patients with LTBI are unable to suppress the infection and develop active TB disease. From a bacteriological standpoint, it appears that delivering intact antigenic proteins is a significant component to illness progression. M. tuberculosis genes hypothesized to be involved in the formation of immunodominant CD4+ T cell antigens do not differ between strains and lineages, suggesting that M. tuberculosis could benefit from antigen-specific CD4+ T cell activation in humans, according to genomic investigations of clinical isolates. (Comas et al.2010). The HIV-TB epidemic lends indirect support to this idea; whereas HIV is definitely a risk factor for progression from LTBI to active TB disease in an individual, HIV/AIDS is adversely linked to contagion. (Corbett et al 2006). Immunodominant antigens are important for a variety of reasons, including understanding disease pathophysiology and developing a vaccination strategy. Identifying immunodominant M. TB antigens and producing a repertoire of M. tuberculosis-specific T cells has long been thought to be the cornerstone for T cell-mediated protective immunity and, thus, an efficient vaccine-based strategy.

In a human investigation, however, a vaccination based on an immunodominant M. tuberculosis antigen failed to improve protection while providing a small degree of better T cell-mediated responses. (Tameris et al 2013). We still don't know the exact basis for BCG protection, or whether it's mediated by CD4+ T cells or by innate immunological pathways, after nearly a century of BCG vaccination. (Abel et al 2014).

1.1.2 Medical need for new drugs The discovery and development of the maximum

successful 4-drug remedy routine to cure drug-prone tuberculosis occurred mid of the nineteenth century. (DS-TB). Isoniazid (H), rifampicin (R), pyrazinamide (Z), and ethambutol (E) were amongst the drugs used. (Zumla A, et al 2013). The introduction of rifampicin in 1960, in instance, changed into hailed as a big enhance as it reduces the remedy time from eighteen to 9 months. The reintroduction of low-dose pyrazinamide allowed for the advent of the prevailing six-month ‘brief-term' remedy routine. (Zumla AI et al 2014). Despite the introduction of fluoroquinolones into MDR-TB remedy regimens, there has been minimum activity within the improvement of more superior anti-TB medication remedy regimens between 1960 and 2000. DS-TB has a top notch remedy charge of 86 percentages. (Zumla A et al 2013). The next challenge is to improve MDR-TB/XDRTB remedy, which remains no longer nicely advanced sufficient to reap a first rate remedy price and is responsible for a big wide variety of human tragedies. In many regions, even if MDR-TB can be recognized, the WHO's fashionable MDR-TB treatment routine may not be to be had. MDR-TB remedy prices are just about half of of what they used to be. As a result, sizeable advancements in diagnosis and therapy are required.

The gift treatment regimens for tuberculosis have some of flaws. With starters, for DS-TB, the prolonged treatment period (six to 8 months), the intricacy, and extreme medicine reactions related to the anti-TB routine bring about extensive non-adherence fees. Treatment failures, prolonged infectiousness, resistance, relapses, or even persistent cases end result because of this. (Van den Boogaard J et al 2009). Second, MDR-TB and XDR-TB treatment regimens are appreciably more costly, harmful, and useless than DS-TB remedy. Treatments for MDRTB and XDR-TB are regularly no longer evidence-based. MDR-TB/XDR-TB treatment takes an inordinate amount of time (18 to 24 months) and medications are frequently unavailable in many impoverished nations (Zumla A et al 2013). Third, due to non-adherence, overlapping toxicity profiles, drug-drug interactions, and the risk of immune reconstitution syndrome in HIV-TB patients, concurrent use of anti-HIV medicines has triggered main control issues (Narita M et al 1998). Fourth, modern-day isoniazid-based totally preventative remedy for latent tuberculosis concerns non-adherence. Last but not least, there is usually a dearth of effective susceptibility trying out for first- and second-line medicinal drugs. As a end result, the remedy regimen is selected primarily based on first-class preparation as opposed to knowledge. With the launch of the Gene expert, it is now possible to diagnose rifampicin resistance speedy, but


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now not resistance to 2nd-line remedies. As a end result, converting remedy plan might not usually be the exceptional choice.

In principle, new chemotherapeutic medications ought to be capable of address the troubles stated above with contemporary remedy regimens. They must preferably lessen remedy periods, be effective in opposition to MDR-TB and XDR-TB, use exceptional Mtb modes of action, permeate all human tissues wherein Mtb is general, have lower toxicity profiles, higher synchronise with antiretroviral therapy (ART), and be active towards latent TB bacilli. (Albanna AS et al 2013).

Scientists, funding our bodies, the WHO's Stop TB Department, and different organizations were operating together to break the stalemate in the improvement of latest anti-TB remedies in the year 2000. (Zumla A et al 2013). Repurposed and extensively to be had pills (e.g, thioridazin, fluoroquinolones, linezolid, meropenem-clavulanate), re-engineered pharmaceuticals, and novel compounds are all presently being advanced (preclinical and clinical phase of development).

More ever, the Food and Drug Administration (FDA) located un USA and the European Medicines Agency (EMA) have sanctioned the new drugs, bed aquiline and delaminid, which might be currently present in the market for treating MDR-TB (Albanna AS et al 2013).

1.1.3 New Regimens in Clinical Trials For new medications to enter clinical trials, they must

demonstrate perceived improvements over existing regimens in a variety of ongoing, finished, and prospective experimental investigation of TB regimens having drug resistance and susceptibility. These advantages are; the short time for treatment which is less than five months for drug-susceptible TB and less than 18–24 months for drug-resistant TB, more efficient working of drugs, less side effects and no interaction between the drugs. In Phase II studies, the newly discovered regimens are new treatment period which are aimed safe to use and bearable, the most promising regimen is advanced to Phase III trials for corroborative efficaciousness and tolerance assessments. Traditional and randomized trial designs with treatments groups of 2 or 3, with sampling size starting from three hundred to one thousand per each group, and 12- to 18-month follow-up after treatment completion are used in these Phase III trials (Nunn et al 2010). Relapse timing in tuberculosis short-course chemotherapy trials. Considering the multiple possible drawbacks in this strategy; extending from the toxicity problems (which are not expecting) when the medicines are combined with complexities of exiting treat methods which are primarily aimed to a long-lasting sterilizing activity instead of rapid bacteria killing action. The probability of attrition is considerable, that is unable to be properly quantified using EBA or Phase IIb designs of trial. After expressing efficiency and tolerance, even after that, traditional Phase III studies and these are demonstrated one by one in sequence with a large number of sample size and also

following up for the long time, taking several years might possibly or more to complete before a new medicine is approved. It took years of hard work and multiple clinical trials to produce the present ‘short course' TB treatment regimen.

2 Development of drug The search for new anti-TB medications has gotten a

lot of attention in recent years. Several options are being studied, and the present pipeline of prospective medications includes a diverse set of chemicals (Comas et al 2010). The molecular processes of mycobacterial persistence and latency must be elucidated. There is multiple strategies required for the development of anti tuberculosis drugs as shown in table 1.

Table 1: Required properties of new anti-TB drugs What a new drug should do Characteristic(s) required

Reduce the length of treatment or simplify it.

Strong bactericidal and sterilizing action combinations with a low pill count and a fixed dosage Allow for sporadic therapy.

Possess a tolerable toxicity profile

Treatment-limiting adverse effects are uncommon. There is no toxicity profile overlap with other anti-TB medicines.

Be proactive in the fight against MDR/XDR TB

No parallel resistance side by side with first-line drugs

Might be good in HIV and TB positive individuals

Other drugs having only a few interactions. There is no toxicity profile overlap with antiviral medications.

Be proactive in the fight against latent tuberculosis.

Activation of latent bacilli toxicity profile that is favorable.

Find and develop new antibiotics with novel modes of

action that are good against persistent bacteria (Dey et al 2014). Develop and validate animal models that accurately anticipate the length of human treatment. Develop and validate efficacy-predicting biomarkers and surrogate outcomes and, as a result, reduce the length of clinical trials. Develop novel preclinical methods for discovering optimal medication combinations, as well as novel clinical and regulatory methods for evaluating drug combinations in phase 2 and 3 clinical trials. Increase the capacity of high-burden countries to conduct clinical trials (Lange C et al 2014).

Recent advancement and future perspective for treating TB which is resistant to many drugs (Heyckendorf J et al 2014).


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Figure 1: New Tuberculosis drug Pipeline

Emerging Drug for development of Tuberculosis Table 2: The drugs approved in Recent Period Name of drug

Chemical test Site of action

Effect Clinical status

Bed aquiline

Diarylquinoline ATP synthase

Stops the energy breaking and making reactions of cell

Phase III

Delaminid Nitroimidazole Exact site of action is unknown yet

Stops preparation of mycolic acid (keto and methoxy mycolic acids) and the mechanism of cell respiration

Phase III

Table 3: Antibiotics used for clinical investigation of Phase II and Phase III Name of antibiotics

Chemical test Action site Effect Clinical status

Q203 Imidazopyridine Cytochrome bc1 complex

Stops synthesis of ATP

Phase II

Pretomanid Nitroimidazole Exact target not yet known

Involved stopping in cell wall synthesis and poisoning by respiration

Phase III

Delpazolid Oxazolidinone 50S subunit of ribosome

Inhibits protein synthesis

Phase II

Sutezolid Oxazolidinone 50S subunit of ribosome

Stops preparation of the protein

Phase II

PBTZ169 Benzothiazinone DprE1 Affects the preparation of protein

Phase II

SQ109 Diamine MmpL3 Synthesis of Protein is inhibited

Phase II

3 Mode of Action of Drugs 3.1.1 BEDAQUILINE In 2012, the Food and Drug Administration (FDA) approved bedaquiline for treating of TB having resistance to many drugs. Sirturo is a brand name for it. Bed aquiline is a member of the diarylquinolines class of antitubercular medicines that is a relatively new class of pharmaceuticals (Koul A et al 2007). Furthermore, adding bed aquiline to the current MDRTB standard treatment regimen has demonstrated to be both cost-efficient and cost-saving (Wolfson et al 2015). Table 4: The list of drugs repurposed

Antibiotics Chemical class

Action site

Effect

Clofazimine

Riminophenazine

The exact action site is unknown yet

Transmembrane penetration and intracellular redox cycling

Levofloxacin

Fluoroquinolone

DNA gyrase

Affects the replication of DNA

Moxifloxacin

Fluoroquinolone

DNA gyrase

Stops the replication of DNA

Linezolid Oxazolidinone 50S subunit of ribosome

Stops the synthesis of protein

Bed aquiline, unlike other medications, targets mycobacteria's energy metabolism. Although it is proposed that mycobacteria can thrive in harsh situations like in deficiency of oxygen but not the all types of mycobacteria either it is dormant or active, involved in fermentation or not, living inside or outside of cell, may need the synthesis of ATP molecules (energy molecules) by ATP synthase to survive (Berney M et al 2010).


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Bedaquiline's ability to kill both reproducing and dormant germs could cut down on the time it takes to cure tuberculosis. 3.1.2 Mechanism of action of Bedaquiline M. tuberculosis' membrane bound ATP synthase enzyme is inhibited by bedaquiline. The transmembrane electrochemical ion (H+ or Na+) gradient is used by ATP synthase to convert ADP to ATP. In the c subunit of ATP synthase enzyme, the sites of interaction of charged particles have outer boundary and produce the energy required for ATP synthesis. Bedaquiline inhibits the proton pump by blocking these ion binding sites, resulting in lower intracellular ATP levels.(Tran SLet al 2005). According to a recent study, bedaquiline targets the FATP synthase subunit via binding with Trp16 residues, in addition to the c subunit (Kundu S et al 2016). ATP synthase is a highly conserved enzyme found in both prokaryotes and eukaryotes that creates ATP through oxidative phosphorylation. (Von Ballmoos C et al 2008).

Figure 2: The interaction of bedaquiline (shown in green) with the Mycobacterium phlei ATP synthase in c-ring In comparison to human ATP synthase, bedaquiline is highly selective for ATP synthase enzyme of Mycobacteria and it has twenty thousand times less efficiency as shown in (Figure 2) (deJonge MR et al 2007). Possibly, due to this reason, it has chances of toxic effects on individuals who are targeted (Haagsma AC et al 2009). Bedaquiline's structure and mode of action differ from those of other antituberculosis medications, reducing the risk of cross resistance. Bedaquiline, according to studies, functions as a proton uncoupler, disrupting the proton gradient across the mycobacterial cell membrane.(Feng X et al 2015) 3.1.3 DELAMANID Delamanid is a nitroimidazole-class medication licensed by the European Medicines Agency to treat MDR-TB infection (Matsumoto M et al 2006). Delamanid has the lowest minimum inhibitory concentration of any of the clinically licenced TB medicines, and it is effective against both types of strains of Mtb either it is sensitive or resistant to drugs. Extracellular and intracellular isolates,

as well as reproducing and dormant cells, are all inhibited by the treatment. However, because both delamanid and bedaquiline are cardiotoxic, WHO does not suggest using them together. They produce QT prolongation, which is a change in the heart's electrical activity. 3.1.4 Activity mechanism of Delamanid Delamanid has been shown to stop the formation of two important mycolic acid components: methoxy and keto mycolic acid. Because mycolic acids are exclusively present inside cell walls of mycobacteria and absent inside the cell walls of other Grampositive or Gramnegative bacteria, delamanid's inhibitory activity is limited to mycobacteria. Because these acids make it difficult for drugs to penetrate the cell wall of mycobacterium, breaking the cell wall allows for improved drug penetration and hence a shorter treatment schedule(Glickman MS et al 2001). Delamanid is a prodrug that must be activated by lowering groups of nitrogen using the deazaflavin (F420)dependent nitroreductase (Ddn) enzyme (Field SK et al 2013). By this enzyme activity, Delamanid is changes into its inactive form called desnitro derivative. But this type of change also releases many other by-products which may increase the efficiency of delamanid (Liu Y et al 2018). Production of Nitric oxide active radicals, for example, are vital for mammals’ immunity to defend the infections caused by Mycobacteria and these types of radicals may also have inhibitory action against delamanid (Xavier AS et al 2014). The precise target of delamanid is still unknown. It's difficult to pinpoint delamanid by examining mutations since the mutants that showed resistance had mutations in genes involved in delamanid activation rather than genes involved in mycolic acid synthesis( Liu Y et al 2018). Mutations in these five genes have been found to be closely connected to delamanid resistance (ddn, fgd1, fbiA, fbiB, and fbiC). These genes have effect on the activation of prodrugs or are involved in the production of the cofactor F420 (Haver HL et al 2015). 3.1.5 Q203 Q203 is an animidazopyridine amide that was discovered via phenotype high content throughput screening and presently being investigated for phase II study experiments. M. tuberculosis MDR and XDR strains were discovered to be resistant to the chemical. (Pethe K et al 2013). In mice, Q203 showed promise against TB. Aside from that, Q203 lacks a chiral core, which facilitates in the compound's large-scale synthesis.(Pethe K et al 2013). The low cost of items necessary production of Q203 at commercial level provides the compound an additional advantage, as TB is a disease that mostly affects low-income countries. (Pethe K et al 2013). 3.1.6 Mechanism of action of Q203 M. tuberculosis generates energy through oxidative phosphorylation in its electron transport chain. (Cook GM


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et al 2015). The complex of cytochrome bcc (also known as cytochrome bc1) is a parts of transport chain of electron found in Mycobacterium TB that catalyses electron transfer from ubiquinol to cytochrome c. (Pethe K et al 2013; Kang S et al 2014). M. tuberculosis is compelled to employ cytochrome bd, which is known to help bacteria protect themselves under stressful settings. Q203 possesses antibacterial properties as a result of this.(Kaliaa NP et al 2017). A recent research proposed about inhibition activity Q203 could be increased if we target cytochrome bd and bcc, simultaneously (Kim M et al 2015). There are significant differences between M. tuberculosis cytochrome bcc and human mitochondrial cytochrome bc1. Because of these distinctions, as well as the truth that cytochrome bcc is needed for survival of Mtb and also a suitable target site against the medicines of TB (Kim M et al 2015). 3.1.7 PRETOMANID Pretomanid, like delamanid, is a medication in the nitroimidazole class. Like other drug, pretomanid, has efficiency for anti-tuberculosis infection that are both replicating and nonreplicating. (Stover CK et al 2000). Both of these novel anti-TB medications must be activated because they are prodrugs with the same activity. Pretomanid is bio reductively activated by the Ddn enzyme, resulting in the formation of different metabolites through the reduction of the imidazole ring. Des-nitro derivative is one of the secondary products ans is involved in destruction of the proteins present inside the cell, lipid parts of cell wall, the large molecules and is bactericidal for anaerobic bacteria. The antimycobacterial activity of pretomanid is thought to be due to its desnitro derivative. However, investigations suggest that pretomanid kills aerobic bacteria by disrupting the cell wall mycolic acid production pathway, which causes ketomycolates to be depleted and hydroxymycolates to accumulate (Singh R et al 2008). Pretomanid has a dual method of action, inhibiting cell wall production while also harming the respiratory system. 3.1.8 Mechanism of Pretomanid Mechanisms explain how pretomanid works on reproducing bacteria, but they don't explain how it works on latent cells. Pretomanid has a better pharmacokinetic profile than delamanid. The absorption rate of this drug is rapid, highly tolerated, and has a high bioavailability. Pretomanid has a long period of half-life of about 16-20 h, therefore it only needs to be taken once a day. (Ginsberg AM et al 2009). Presently, the clinical trials of pretomanid being investigated under phase III. 3.1.9 Sutezolid In 1996, sutezolid was developed with linezolid. After a long period of development, sutezolid, the second most promising oxazolidinone candidate after linezolid, was discovered to be active against Mycobacterium

tuberculosis. In rodent models, this medication proved effective against treatment-resistant M. tuberculosis strains and had good pharmacokinetics and low toxicity. It was tested on people after demonstrating promising outcomes in murine models, and it looked to be safe and well tolerated. (Wallis RS et al 2010). In comparison to linezolid, sutezolid has a higher efficacy against M. tuberculosis.(Williams KN et al 2009). Because of its poor toxicity profile, linezolid is only used to treat drug-resistant tuberculosis.(Kishor K et al 2015). On the other side, Sutezolid is good and safe to be used and is 1–2 orders of magnitude has better efficiency against Mtb infection than linezolid.(Cynamon MH et al 1999). According to these research, sutezolid can be considered a good agent for treatment of tuberculosis than linezolid. Currently, the phase II trials of sutezolid has been done in a good way, but due to licencing concerns, certain stage 1 studies are being repeated. (Tiberi S et al 2018). 3.1.9.1 Mechanism of Sutezolid Linezolid has a comparable mechanism of movement. The attachment of 23S unit of ribosomal RNA to sutezolid prevents protein production. Sutezolid is changes into its actively working form called sulfoxide by-products, that's greater powerful against extracellular tuberculosis than sutezolid. The unique chemical, sutezolid, became located to be 17 times greater efficient than its metabolite in treating the TB caused in both inside of cell and lungs (Zhu T et al 2014). Furthermore, sutezolid is effective towards both drug-inclined and drug-resistant tuberculosis.(Alffenaar JW et al 2011). Because both the drugs and its metabolite have a quick plasma 1/2-lifestyles (approximately 4 hours), a divided dose is preferred over a unmarried dose. (RS Wallis et al 2014). Sutezolid works with SQ109 and has better efficiency while used with the other newly made anti-TB capsules (Reddy VM et al 2012). Researchers found out that combining sutezolid with SQ109 and bedaquiline has additive results in wholeblood studies and may be utilized for treating tuberculosis which is drug susceptible and resistant (Wallis RS et al 2012). 3.1.9.2 PBTZ169 PBTZ169 is a benzothiazinone (BTZ) medication that is now being tested in phase II early bactericidal activity trials.(Tiberi S et al 2018). PBTZ169 is a piperazinobenzothiazinone that was created by improving the benzothiazinone class's lead molecule, BTZ043. In vitro screening of chemicals for antibacterial and antifungal activity led to the discovery of BTZ043 (Makarov V et al 2006). Due to the lack of chiral centres, PBTZ169 has many benefits compared to BTZ043, and one them is the easy synthesis and better pharmacodynamics. PBTZ169 is more resistant to nitroreductase attack than other BTZs due to the inclusion of a cyclohexyl group (Makarov V et al 2014). Against


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MDRTB strains, PBTZ169 and BTZ043 show promising bactericidal action. Both medication possibilities are highly effective against replicating bacteria but have little effect on non-replicating bacteria (Yuan T et al 2018). Bedaquiline and PBTZ169 have synergistic effects (Makarov V et al 2014). BTZ043 is under preclinical development, while this drug has been found in progressive stages of phase II experimental study (Tiberi S et al 2018). 3.1.9.3 Mechanism of PBTZ169 The DprE1 enzyme is targeted by PBTZ169, like other BTZs with DprE1, PBTZ169 forms irreversible covalent adducts (Yuan T et al 2018). The nitro group of PBTZ169 is thought to be reduced to generate a derivative of nitroso that has covalent bonds with the residues of cysteine in action site of DprE1 to form an irreversible adduct that inhibits DprE19.(Trefzer C et al 2010). DprE1 inhibition inhibits the synthesis of decaprenylphosphoryl arabinose, a crucial component involved in the preparation of cell wall of Mycobacteria arabinans which causes breaking of cell which eventually causes the death of cell (Tiberi S et al 2018). 3.1.9.4 SQ109

SQ109 is 1, 2‐ethylenediamine and presently has been found in experimental study of phase II for drug susceptible TB (Sacksteder KA et al 2012). The MmpL3 protein of Mycobacterium TB, which is worried in cellular wall manufacturing, is the target of this healing candidate.(Tahlan K et al 2012). The shape of SQ109 turned into inspired by ethambutol, a famous first-line medication in treating TB. Ethambutol was chosen since it could not be thoroughly evaluated when it changed into observed in 1961 due to a loss of combinatorial chemistry tools on the time.(Rockville, MD) and the National Institute of Allergy and Infectious Diseases' Laboratory of Host Defenses evolved a large chemistry lab of ethambutol analogues incorporating 1,2 ethylenediamine as a pharmacophore and examined their attentiveness for Mtb. SQ109 changed into observed as a result of this. SQ109, alternatively, is lively against ethambutol-resistant strains, indicating that its mode of movement differs from that of ethambutol (Sacksteder KA et al 2012). SQ109 is bactericidal towards M. Tuberculosis traces that reason

Figure 3: Structure‐activity relationship of clofazimine. TB, tuberculosis MDRTB and XDRTB (Jia L et al 2005). According to in vitro research, SQ109 has combined influence with rifampicin and isoniazid, as well as additional results with other drugs (Chen P et al 2006). SQ109 also improves bedaquiline's in vitro hobby through 4 to eightfold (Reddy VM et al 2010). 3.1.9.5 Mechanism of action of SQ109 In the cytoplasm, mycolic acids are produced and sent back to outer part of cytoplasm and here they are next transported and absorbed into the cell wall. Trehalose is required for the export of mycolic acids. In the cytoplasm, both trehalose and mycolic acids are thought to produce conjugates, which are then transported to the mycobacterium cell wall.This export pathway is aided by the MmpL3 protein (Varela C et al 2012). 3.1.9.6 Clofazimine Clofazimine is an antileprosy medication that has been repurposed for the treatment of MDRTB. It belongs to the riminophenazine class of antibiotics.(Lechartier B et al 2015 ). The medicine was originally created to treat tuberculosis and is sold under the brand name lamprene. Clofazimine has strong antimycobacterial action in vitro, but it was discontinued since it was discovered to be therapeutically ineffective in humans, causing skin discoloration and mental problems (Reddy VM et al 1999). The same time invention of superior drugs involved in treating TB infections caused the lack of interest of scientist in efficiency of clofazimine drugs against Mtb infections . However, the World Health Organization (WHO) endorsed clofazimine for the treatment of multidrug-resistant leprosy in 1981. (Dey T et al 2013). Later, as the DRTB pandemic spread, there was renewed attention in clofazimine, which plays important role in current treatment period of TB.(Nunn AJ et al 2014). Clofazimine, in addition to having antibacterial qualities, also has antiinflammatory effects, making it useful for treating nonmicrobial and inflammatory cutaneous conditions (Rensburg CEV et al 1992). 3.1.9.7 Mechanism of action of clofazimine Clofazimine is a pro-drug, and the precise activity of this drug is unknown yet. According to studies, clofazimine is reduced by type 2 NADHquinone oxidoreductase (NDH2) and subsequently reoxidized to produce reactive oxygen species (ROS) (Yano T et al 2011). NDH2 is an oxidoreductase enzyme found in the respiratory chain of mycobacteria. To start respiration, this enzyme utilises menaquinone as a substrate. Clofazimine competes for electrons via menaquinone and undergoes reduction. After, clofazimine is oxidised, releasing reactive species of oxygen like Figure 3: Structure‐activity relationship of


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clofazimine. TB, tuberculosis H2O2 and superoxide (Grant SS et al 2012). M. tuberculosis is controlled in part by reactive oxygen species (ROS). ROS are produced as a byproduct of normal respiration and are eliminated by antioxidants. However, excessive ROS production disturbs the balance reactive species of oxygen antioxidants, resulting in oxidative stress. By breaking down nucleic acids, proteins, lipids, and other macromolecules, these ROS radicals kill cells (Howell Wescott HA et al 2017). Although this redox cycling process explains why activity of clofazimine against bacteria does not drop significantly in hypoxia, it does not explain why it does not decrease significantly under anaerobic conditions (Lu Y et al 2011). As a result, researchers came to the conclusion that clofazimine has distinct modes of action depending on the environment. Furthermore, menaquinone has the ability to stabilise secondary membranes, which may help it overcome the drug's disruptive effect on bacterial membranes (Nazarov PV et al 1996). It's also unclear why Gramnegative bacteria, which are vulnerable to ROS' antimicrobial actions, aren't affected by clofazimine (Cholo MC et al 2012). These data point to clofazimine's multifarious or alternative modes of action. Due to overexpression of the MmpL5 efflux pump, clofazimine also exhibits crossresistance with bedaquiline. Bedaquiline and clofazimine crossresistance has recently been linked to mutations in the pep Q gene. (Hartkoorn RC et al 2014). 3.1.9.8 Moxifloxacin Moxifloxacin is a fluoroquinolone antibiotic that is used to treat MDR tuberculosis. (Bryskier A et al 2002). Currently, the medicine is being studied in combinations of bedaquiline, pretomanid, and pyrazinamide, as well as rifapentine. Recent studies are supporting in using this drug in treating the individuals who're illiberal to or resistant against the first-line tablets of TB, although it does now not appear like powerful in decreasing the regimens of treatment. The pharmacokinetics of moxifloxacin differs from person to person.(Rodriguez JC et al 2001). 3.1.9.9 Mechanism of action of Moxifloxacin The blockage of DNA gyrase production, involved in inhibition of DNA replication of bacteria, is liable for moxifloxacin's bactericidal pastime in mycobacteria (A.S. Ginsburg et al 2003). The DNA strand is broken by the enzyme DNA gyrase, which forms a DNA complex. Moxifloxacin, like other fluoroquinolones, joins and stabilises enzyme DNA molecule, making the complex of a drugenzymeDNA. This halts the replication fork's progress, resulting in chromosome fragmentation. Gatifloxacin, another fluoroquinolone, functions in a similar

fashion (Malik M et al 2006). 3.2 LINEZOLID Linezolid is an oxazolidinone antibiotic that become to begin with authorised in 2000 for the remedy of Gram-fantastic bacterial infections inclusive of methicillin-resistant Staphylococcus and Vancomycin-resistant enterococcus. This product's brand name is Zyvox. (G. Sotgiu et al 2015) E. I. du Pont de Nemours & Company found the first oxazolidinone contender in 1978. However, further development of this family of antibacterials was halted due to safety concerns, particularly hepatotoxicity, in clinical studies. In later 1990s, resistant in Grampositive bacteria has motivated the scientist to create oxazolidinones, having safe and better quality. After many years of discovery of oxazolidinones, in 2000, the first oxazolidinone medicine called linezolid was approved by FDA for clinical trials (Douros A et al 2015). Later research revealed about medicine efficiency for both Gram-positive bacteria and mycobacteria (Jadhavar PS et al 2015). All medications in the oxazolidinone class are synthetic antibiotics that suppress protein synthesis by acting on the 50S ribosomal subunit of bacteria (Lin AH et al 1997). Linezolid is a medication of choice for the treatment of tuberculosis because it has no crossresistance with other clinically approved antituberculosis medicines and has great oral absorption. (Jadhavar PS et al 2015). Delpazolid and sutezolid, two newer oxazolidinone possibilities, are currently under clinical investigation. Both Delpazolid and sutezolid has less hazardous effects compared to linezolid and also are very efficient (Tiberi S et al 2018). 3.2.1 Activity mode of Linezolid The antibiotic linezolid has been found to stymie ribosome's ability to produce protein (Livermore DM et al 2003). The ribosome of bacteria has a huge complex of nucleoprotein, having the other two small parts called 30S (small part) and 50S (large part). Every small parts has ribosomal RNA (rRNA) and also the ribo protein (rproteins) which both are involved in making the cell protein (Poehlsgaard J et al 2005) (Zumla A et al 2013). Initiation, elongation, termination, and recycling are the four phases of production of protein. The A, P, and E sites on ribosomes are three different portions involved in protein synthesis. In the beginning, both small (30S) and large (50S) components of ribosome join together forming a 70S ribosome and messenger RNA (mRNA) is located on transfer RNA (tRNA) on the P- web page for the formation of peptide‐bond (Wilson DN et al 2014). The aminoacylated tRNA (aatRNA) is transported to the Asite of the ribosome during the elongation phase. The amino acids linked to the A and Psites tRNAs create peptide bonds as a result of this. The constant transportation of amino acids from P to A site is done, resulting in peptide chain elongation and egress to the cytoplasm via the Esite. After that, the components are recycled, and the


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cycle begins all over again (Jadhavar PS et al 2015). The aminoacyl residue of aatRNA is taken up by linezolid when it attaches to the A site of the 50S peptidyltransferase centre (PTC). (Livermore DM et al 2003). 4 Drug Resistance against tuberculosis In 1948, in the course of the first human trial of TB therapy, the phenomenon of drugs resistance turned into to begin with defined in the infectious disease tuberculosis (TB) (Daniels et al 1952). As each new anti-TB treatment is brought into scientific guidance, the spread of resistance strains is found, usually with a year. M. Tuberculosis improves resistant to antibiotics due to genus changes (there are not any reports of resistance developed by the acquisition of recent DNA). Despite the fact that the variety of genes linked to resistance is rising all of the time, allelic exchange checks have only validated the causality among mutation and drug resistance for a fraction of altered genes (Nebenzahl-Guimaraes et al 2014). In those genes, the main 2 processes of drugs resistance are the changes in active site (as an instance, a changed RNA polymerase copy in bacteria which escapes out the action of rifampicin) and also the ineffective enzyme involved in conversion of a pro-drug into an active drug (as an instance, the bacterial catalase enzyme changed by mutation which in unable evade out the action of isoniazid). Drug susceptibility testing, each phenotypic and genotypic, have shortcomings that make it hard to recognize resistance mechanisms. (Solomon et al 2015). Phenotypic assays yield a binary end result (the M. Tuberculosis pressure is both sensitive or proof against a particular remedy dose) and are quality standardised for a small range of medicine (for example, isoniazid, rifampicin and ethambutol). Furthermore, genotypic drug susceptibility testing might also overlook a mutation in a phenotypically resistant isolate. Finally, finding a mutation in a phenotypically resistant isolate through gene or genome sequencing does no longer routinely imply locating the underlying mutation that causes the resistance. The found mutation should contain any of the following mutations: causative, stepping-stone, compensating, or supplementary (this is, merely a marker of the strain circulating in that unique setting. To place it any other way, the recognized mutation on my own won't be enough to motive pharmaceutical resistance. In order to locate medication resistance, diagnostic strategies ought to handiest use causal mutations. As a end result, it's essential to recognize what shape of mutation has been located. To this stop, numerous companies have started to carry out entire-genome sequencing on clinical isolates, with the quick-time period intention of figuring out novel resistance-related mutations and the long-term purpose of developing a test that might hit upon resistance quicker than tradition-based totally drug susceptibility exams and update them (Walker et al 2015). Although studies show that this era is

sensible, it has low susceptibility (there are nevertheless physically resistant isolates for which mutation involved has no longer been detected). (Bradley et al 2015) Considering high prices, lifestyle-based totally assays are nonetheless an vital part of clinical education (Dominguez et al 2016). 4.1.1 NEW DRUGS DEVELOPMENT CHALLENGES A number of roadblocks have slowed the development of new anti-TB medications. To begin with, the TB drug market is linked to lacking of investment return and opportunity of profit return that encourages drug companies for production of other drugs. A new drug's development costs are expected to be between $115 and $240 million (Gardner et al 2010). The difficulty of identifying novel compounds with action against Mycobacterium tuberculosis is a second hurdle in TB medication development. TB treatments should eliminate mycobacteria which grow rapidly (having bacterial killing ability) and persistent mycobacteria present in pus (sterilising activity) (Mitchison et al 2010). Mycobacterial dormancy (mycobacteria which are sensitive to drugs and remain alive inspite of common exposing to drugs for TB), persistence (drug-susceptible mycobacteria that survive despite frequent exposure to TB medications), and resistant to drugs are all molecular mechanisms that remain unclear (Zhang et al 2004). The next hurdle will be evaluating new compounds, as there are currently no animal models that can properly predict the required treatment period for newly discovered compounds (Mitchison et al 2005). Because it more closely resembles the pathogenesis of tuberculosis in people, the guinea pig model is being studied as an alternative to the mouse model (Karakousis et al 2008) A dearth of trial sites with the research ability to conduct large-scale clinical trials is another challenge. Trials should be done in countries with the highest TB prevalence, but human and infrastructure capacity for large, high-quality phase III clinical trials is often limited in these countries (Ginsberg et al 2007). Despite the challenges of developing TB drugs, greater doses of rifamycins are being tested, and a number of prospective treatment candidates have advanced to the clinical testing stage. 4.1.2 Current scenario of development of Anti-Tuberculosis Drugs Patients with tuberculosis have obtained the same popular remedies for the beyond 5 decades, notwithstanding variations in human immunity, pharmacokinetics, or variations in aetiology or the causative micro organism. Mycobacterium tuberculosis is a bacterium that causes tuberculosis. Treatment was either ad hoc or based on the results of phenotypic drug susceptibility testing, which might take weeks or months to complete. Mostly in young patients, patient-tailoring was limited to adapting dose to body weight. We have now entered an exciting technology


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of medicine, with big enhancements in the subject of system biology, and it is reasonable to count on that tuberculosis sufferers will advantage notably from these advancements.(Lange C et al 2018). In the future, tuberculosis affected person care can be individualized in at least 4 areas (I) In the first week after diagnosis, next-generation sequencing of microbial M. tuberculosis DNA can predict treatment susceptibility (Consortium CR et al 2018). II Host immunity might be detrimentally reduced and want

to be augmented, or it may be detrimentally exuberant and want to be inhibited (DiNardo AR et al 2020) or other styles of host genetic variability that may be addressed specially by means of immune-based totally healing procedures. (Abel L et al 2018). (III) Antimicrobial dosing can be guided by individualised medication concentrations (Magis-Escurra C et al 2012).

Figure 4: In the near future, Precision Medicine for tuberculosis will likely include (I) antibiotic regimens based on next-generation sequencing of the Mycobacterium tuberculosis genome to guide tailor-made therapies; (II) evaluation of gene expression, genetic, epigenetic, metabolism, and/ or immune phenotyping to discern the host endotype with endotype-specific host directed therapies to shorten and improve clinical outcomes; (III) individualization of antibiotic dosing through therapeutic drug monitoring; (IV) in treatment biomarker levels to customize therapy duration. LAM, lipoarabinomannan; Mtb, Mycobacterium tuberculosis; INH, isoniazid; LSS, limited sampling strategy; HPLC-MS, high-performance liquid chromatography-mass spectrometry; AUC, area under the curve; MIC, minimal inhibitory concentration; TB, tuberculosis.

(IV) Biomarkers that indicate relapse-free remission and can help determine the length of time necessary for traeatment (Heyckendorf J et al 2014). Such stratified medicines are within reach and may soon be offered for tuberculosis clinical care. Precision medicine refers to preventative and treatment measures that account for individual variability and predict mutations. Genotypic DST could potentially replace phenotypic DST for a large percentage of clinical M. tuberculosis complex strains.

CONCLUSION AND FUTURE PERSPECTIVES Since Mycobacterium tuberculosis (Mtb) is the most successful pathogen known to humans, and medication resistance has become a major challenge, new therapeutic strategies to combat this problem are required. Precision medicine for tuberculosis patients is now possible thanks to technology advancements in finding the reasons of disease, and the integration of large data sets at facilities on the cutting edge of translational research. Genotypic prediction of phenotypic M. Tuberculosis drug


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resistance based totally on complete bacterial genome records, genotypic and phenotypic identification of immune endotypes and human tuberculosis susceptibility to individualize HDT, and novel biomarkers guiding physicians for man or woman treatment decisions are already in vicinity as independent measures at surprisingly specialised facilities and normally underneath studies conditions as shown in figure 4.( Heyckendorf J et al 2014).The scientific application of some of those innovations desires to come to be the medical wellknown. However, because tuberculosis is a poverty-related disease, the majority of tuberculosis patients live in resource-constrained environments. One of the essential boundaries in the destiny might be finding budget and doing operational research on the adoption of precision remedy for tuberculosis in those settings. CONFLICT OF INTEREST The authors declared that present study was performed in absence of any conflict of interest. ACKNOWLEGEMENT I would like to thanks all the authors to contribute in this manuscript. AUTHOR CONTRIBUTIONS MS and ASM designed and performleed the experiments and also wrote the manuscript. ABS, MB, and SA helped in making figures and table. SS, MAA, RB, MA reviewed the manuscript. All authors read and approved the final version.

Copyrights: © 2021@ author (s). This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author(s) and source are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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