Combating Tuberculosis (TB) is still a tough challenge as TB stands as the number one infectious disease killer and leading contributor to antimicrobial resistance. Exacerbated patient non-adherence to TB medications due to long treatment timelines, harsh side effects, and poor regimen adherence has led to an increase in drug-resistant TB (DR-TB). TB patients with comorbidities like HIV/AIDS are particularly at risk of dying from TB. Despite the extensive global initiatives and the introduction of newer treatment options such as Bedaquiline and Petromanid, emerging and increasing drug-resistant TB (DR-TB) remains a major hurdle to global TB control efforts. Recovery rates are alarmingly low, with nearly 68% for multidrug-resistant Tuberculosis (MDR-TB) and only 30% for extensively drug-resistant Tuberculosis (XDR-TB), underscoring its severity. Updating our understanding of TB and its drug resistance mechanisms is crucial for developing effective strategies and innovative treatments. This book, therefore, focuses on the emergence of resistance in Mycobacterium tuberculosis (M. tuberculosis) strains, the challenges associated with DR-TB, current therapeutic targets, and the novel chemical classes and regimens within the existing TB drug development pipeline.
Table of contents
ABSTRACT
1. INTRODUCTION
2. THE EMERGENCE OF DRUG RESISTANCE IN M. tuberculosis
3. GLOBAL STRATEGY TO END TB
4. IMPACT OF THE COVID-19 PANDEMIC ON TB
5. TB DRUG TARGETS
5.1 Cell Envelope
5.2 GyrA/B
5.3 DnaN
5.4 ATP Synthase
5.5 LeuRs
5.6 QcrB
5.7 DprE1.
5.8 FadD32 and Pks13
5.9 MmpL3
5.10 InhA
5.11 MurI
5.12 KasA
5.13 Efflux pumps
5.14 PurF
6. TB RESEARCH AND DEVELOPMENT
7. CURRENT TB DRUG PIPELINE
8. NOVEL CHEMICAL CLASSES IN CURRENT TB DRUG PIPELINE
8.1 Diarylquinolines
8.2 Nitroimidazoles
8.3 Rifamycin
8.4 Fluoroquinolines
8.5 Oxazolidinones
8.6 Imidazopyridine amides
8.7 Amidopiperidines
8.8 Benzothiazinones
8.9 3,4-Dihydrocarbostyril
8.10 Azaindoles
8.11 Trinem beta-lactums
8.12 Ethylenediamines
8.13 Riminophenazines
8.14 Oxaboroles
8.15 Pyrimidines
8.16 Tetrazoles
8.17 Pyrrolidinopyrimidines
9. CONCLUSION
REFERENCES
ABSTRACT
Combating Tuberculosis (TB) is still a tough challenge as TB stands as the number one infectious disease killer and leading contributor to antimicrobial resistance. Exacerbated patient non-adherence to TB medications due to long treatment timelines, harsh side effects, and poor regimen adherence has led to an increase in drug-resistant TB (DR-TB). TB patients with comorbidities like HIV/AIDS are particularly at risk of dying from TB. Despite the extensive global initiatives and the introduction of newer treatment options such as Bedaquiline and Petromanid, emerging and increasing drug-resistant TB (DR-TB) remains a major hurdle to global TB control efforts. Recovery rates are alarmingly low, with nearly 68% for multidrug-resistant Tuberculosis (MDR-TB) and only 30% for extensively drug-resistant Tuberculosis (XDR-TB), underscoring its severity. Updating our understanding of TB and its drug resistance mechanisms is crucial for developing effective strategies and innovative treatments. This book, therefore, focuses on the emergence of resistance in Mycobacterium tuberculosis (M. tuberculosis) strains, the challenges associated with DR-TB, current therapeutic targets, and the novel chemical classes and regimens within the existing TB drug development pipeline.
Keywords: Novel Chemical Classes; Anti-TB drugs; Drug-resistant-TB; TB-Drug Targets; TB-Drug pipeline.
1. INTRODUCTION
Tuberculosis (TB) is an airborne and highly contagious disease caused by the bacterium Mycobacterium tuberculosis (M. tuberculosis), ranking as the world’s leading infectious disease killer, surpassing coronavirus disease 2019 (COVID-19) in 2023 [1]. M. tuberculosis is an intracellular parasite that spreads mainly through aerosols expelled by humans with active TB, primarily affecting the lungs, and can disseminate into other parts of the body. Most infections do not cause any symptoms and are referred to as inactive or latent tuberculosis. However, a small portion of these latent infections can develop into active TB, which can be fatal if not treated [2,3]. There were an estimated 10.8 million people who fell ill with TB, and 1.3 million people died, including 161000 people with human immunodeficiency virus (HIV) worldwide, in 2023. The top eight TB burden countries (India, Indonesia, China, the Philippines, Pakistan, Nigeria, Bangladesh, and the Democratic Republic of the Congo) are responsible for more than two-thirds of the global TB incidence [1].
Despite being a preventable and curable disease, TB is the leading cause of death among people with HIV and a significant contributor to antimicrobial resistance (AMR). TB disease mortality is high (~50%) without treatment. Every year, many new cases of TB are attributable to five risk factors: undernourishment, HIV infection, smoking, alcohol use disorders, and diabetes [2]. People living with HIV are 16 times more prone to fall ill with TB than people without HIV. In addition, malnutrition impairs the immune response to TB [3], and the risk of developing TB increases more than 3-fold with diabetes, which is a stronger risk factor than HIV in certain regions [4,5].
The most popular diagnostic technique for TB is sputum smear microscopy, in which sputum samples are observed under a microscope [6]. Besides, culture methods (the current gold standard), sequencing technologies, and rapid molecular tests are also being used for the detection of TB and drug-resistant tuberculosis (DR-TB) [7-9]. Diagnosis of TB co-morbidities is necessary to improve patient adherence. The current recommended treatment (Current standard TB chemotherapy) is effective, and approximately 88% of people can be cured. This includes a 4-6-month duration of a combination regimen that consists of the usage of rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB), also known as first-line drugs, shown in Figure 1. Significant improvement is needed to overcome pitfalls such as high toxicity, low bioavailability, side effects, issues with pharmacokinetics, and pharmacodynamics, which persist in clinical therapeutics.
Figure 1. First-line drugs used in the TB regimen.
Illustrations are not included in the reading sample
Prevention of the infection may include vaccination, and the treatment comprises a new anti-TB drug regimen. As part of the protective measures, the only available and widely used licensed vaccine for TB disease is the Bacillus Calmette-Guerin (BCG) vaccine, which was developed nearly a century ago to avert severe forms of TB in children [10]. Currently, no licensed vaccine is effective against TB infection in adults. Further breakthroughs in vaccine development are vital to successfully controlling M. tuberculosis.
Ending the TB epidemic by 2030 is a key health target outlined in the Sustainable Development Goals (SDGs) [1,11]. Addressing this issue requires concerted efforts in developing new treatments, improving diagnostics, and enhancing healthcare infrastructure to combat M. tuberculosis effectively. The determination of the Mycobacterium tuberculosis H37Rv genome sequence in 1998 was a breakthrough for scientists, backing the discovery of new drug targets and the investigation of resistance developed by the microorganism [12]. This review recapitulates drug resistance in TB, existing challenges in addressing DR-TB, and potential ways to treat DR-TB. It also summarises new TB drugs/drug candidates under development with emphasis on their chemical classes, biological targets, and pharmacokinetic properties.
2. THE EMERGENCE OF DRUG RESISTANCE IN M. tuberculosis
AMR poses a significant challenge to modern medicine and is recognised as one of the top ten global public health threats of the 21st century. It undermines the effectiveness of drugs, restricts treatment options, mainly in infectious diseases, and impacts all areas of oncology [13,14]. The emergence of drug-resistant M. tuberculosis strains is threatening progress in containing the global tuberculosis epidemic [15,16]. Curbing TB is extremely challenging due to its ability to persist inside macrophages, adapt to hostile environments, and resist antibiotics. The magnitude of the infectious disease can be understood from the ‘global TB report 2024’ published by the WHO, which estimated that 175,923 people fell ill with DR-TB (including MDR/RR-TB and XDR-TB) in 2023 [2]. These numbers highlight the complexity that DR-TB presents to modern medicine and global public health efforts.
Drug resistance can be either primary or acquired and arises from several factors contributing to resistance among M. tuberculosis, including mutations in genes, the impenetrability of the cell walls to antibiotics, and M. tuberculosis efflux pumps, among others. Acquired drug resistance stems from the selection of genetic mutants, often deriving from substandard treatment or poor adherence to prescribed therapy by the patient [16]. Hence, the development of drug resistance in M. tuberculosis is highly complex [17-20].
Drug-resistance in TB can be categorised in four distinct types: (i) M. tuberculosis strains that have developed resistance to at least one front-line drug, called single drug resistance (SDR-TB), such as resistance to rifampicin (RR-TB)-the most effective first-line drug–is of greatest concern. (ii) Resistance to rifampicin and isoniazid is defined as MDR-TB (Multidrug resistant Tuberculosis) (iii) TB that is resistant to rifampicin and any fluoroquinolone (a class of second-line anti-TB drug) named as Pre-XDR-TB, (iv) whereas TB that is resistant to rifampicin, plus any fluoroquinolone along with at least one of the new drugs such as bedaquiline and linezolid is called XDR-TB [21]. Globally, an estimated 3.3% of new TB cases and 17% of previously treated TB cases are affected by MDR/RR-TB [2,3].
Historically, Streptomycin (STR), the first drug for TB, was discovered in 1946, and resistance to it emerged as early as 1948 (Figure 2) [22]. Later, the development of resistance to Para-aminosalicylic acid and INH was reported, marking the first case to demonstrate the existence of Multidrug resistance [23]. The emergence of resistance to more than two drugs, namely XDR-TB, was first identified in 2006 and has consistently increased over time. Especially, individuals living with HIV are more susceptible to developing XDR-TB because of their compromised immunity. Main obstacles to drug resistance are prescription of inadequate regimens, insecure drug supply, ineffective drugs, and long duration of treatment (6 to 9 months).
MDR-TB and RR-TB require treatment courses that are longer, relatively expensive, and more toxic second-line drugs, depicted in Figure 3. The global success treatment rate for MDR/RR-TB stands at around 68 % [1]. In addition, MDR-TB often plays a vital role in ‘Post-TB Lung Disease’ (PTLD), which causes disability, as well as necessary rehabilitation for the victims [25]. XDR-TB is a severe form of tuberculosis and has limited treatment options. XDR-TB can develop when second-line TB drugs are improperly used or mismanaged and become ineffective. In addition, TB drugs are not compatible with certain common antiretroviral therapies used to treat HIV. Furthermore, health conditions/factors such as HIV, diabetes, malnutrition, smoking, and alcohol consumption could either prolong or complicate the course of the disease, which in turn leads to co-morbidity to make the treatment more complex. Especially, tuberculosis co-infection with HIV enhances the replication of the virus, which in turn vastly increases the risk of mortality [1,16].
Figure 2. Second-line drugs are used in the TB regimen.
Illustrations are not included in the reading sample
A new 6-month regimen referred to as BPaLM (consisting of bedaquiline (B), pretomanid (Pa), linezolid (L), and moxifloxacin (M)), and the use of 9-month all-oral bedaquiline-containing regimens are used for the treatment of RR-TB /MDR-TB, and the regimen can be used without moxifloxacin (BPaL) for the treatment of pre-XDR-TB as per the latest WHO guidelines, [26]. Treatment for XDR-TB remains much more difficult, and success rates are typically low. The treatment for MDR-TB/XDR-TB will become hard for the low- and middle-income countries (LMICs) [21]. Hence, there is an urgent need to develop a new class of TB drugs with novel mechanisms of action (MoAs), along with associated regimens, to address the challenges outlined above.
Figure 3. Timeline of the emergence of drug resistance
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3. Global Strategy to end TB
The “End TB Strategy” was adopted by all WHO member states at the World Health Assembly (WHA) in 2014, for the complete eradication of the epidemic. It consists of three high-level indicators, targets, and milestones, over twenty years, from 2016 to 2035 [27,28]. The indicators are the number of TB deaths per year, the TB incidence rate, and the percentage of TB patients and their households experiencing catastrophic costs due to TB disease. Related targets set for 2030 (linked to the SDGs), for 2035, and milestones for 2020 and 2025. The End TB Strategy aims for a 90% reduction in TB deaths and an 80% reduction in the TB incidence rate by 2030, compared with levels in 2015. Similarly, targets a 95% reduction in TB deaths and a 90% reduction in the TB incidence rate for 2035. The first and foremost milestone is a 35% decrease in TB deaths and a 20% reduction in the TB incidence rate set for 2020 [27].
The global strategy for TB research and innovation was adopted by the WHA in August 2020, which was developed to sustain efforts made by the governments and non-state partners to accelerate research and to progress equitable access to the benefits of the research. The strategy’s objective is in line with ‘the Moscow Declaration to End TB’ and the WHO ‘End TB Strategy’. It aims to reinforce public-private partnerships and to assist knowledge sharing in TB research and innovation [29]. Support from the WHO is crucial for strategic and technical assistance to member states, ensuring smooth implementation.
4. Impact of the COVID-19 pandemic on TB
Tuberculosis is an endemic infectious disease, with a rise in the number of MDR-TB cases along with the TB-HIV co-infection each year. Like many other areas, TB is also side-lined and negatively affected during the expansion of the coronavirus disease (COVID-19) pandemic. The COVID-19 pandemic has reversed years of progress in providing essential TB services and reducing TB disease burden [30]. Only 5.8 million new TB cases were reported in 2020, which brought the world back to the level of 2012 and partially recovered in 2021 [21]. After two years of COVID-19-related disruptions, there was a major global recovery in TB notification and treatment in 2022. There was a notable rise (~1.4 million) in global TB deaths between 2020 and 2021 [2]. TB caused an estimated 1.30 million deaths in 2022 globally, almost back to the level of 2019. This has started to reverse or moderate the damaging impact of the pandemic on the number of people dying from or falling ill with TB [31]. However, TB remained the world’s top leading cause of death from a single infectious agent in 2023, and global TB targets have either been missed or remain off track [1]. At present, the estimated TB incidence rate is expected to have increased by 4.6% between 2020-2023, reversing declines of nearly 2% per year between 2010-2020 [1].
5. TB Drug Targets
M. tuberculosis has a unique cell wall that consists of saturated long-chain fatty acids or mycolic acids, which present a robust and relatively insoluble barrier. It facilitates the manifestation of either intrinsic or acquired resistance to antibiotics, the mode of action of current drugs, and the mechanisms of bacterial resistance in the pursuit of new anti-TB drugs [18,32]. Anti-tuberculosis drugs with novel modes of action and innovative targets are the key means to solve MDR-TB and extensively drug-resistant TB. The mode of action for the existing and emerging drugs against M. tuberculosis includes inhibition of the cell wall, cell wall acids, and peptidoglycan (WecA) synthesis, DNA gyrase and topoisomerases, DNA replication, protein synthesis, ATP synthase, Lipid synthesis, DprE1, InhA, QcrB, LeuRS, MmpL3 protein, and L, D-transpeptidase, shown in Figure 4 [33]. Here, we provide an insight into emerging targets aimed at challenging difficult-to-treat bacterial strains such as MDR- and XDR-TB.
Figure 4. Identified TB drug targets and their counter drugs and drug candidates
Illustrations are not included in the reading sample
5.1. Cell Envelope
The constituents of the mycobacterial cell envelope: the cytoplasmic membrane, the periplasmic space (PS), a network of peptidoglycan (PG), the arabinogalactan (AG), the long-chain mycolic acids (MA), and the capsule, made of a loose matrix of glucans and secreted proteins.34 MAs are the main integral lipid constituents of the exceptionally fortified waxy cell wall of M. tuberculosis and the primary mediators of hydrophobicity and impermeability thereof. As to the first-line TB drugs, the bactericidal agent INH inhibits MA synthesis, while the bacteriostatic EMB inhibits AG synthesis and may sensitise M. tuberculosis to other drugs [35].
5.2. GyrA/B
DNA gyrase is an evolutionarily stable type II topoisomerase enzyme in M. tuberculosis, crucial for transcription, replication, and recombination. It is an ATP-dependent tetrameric enzyme (with A2B2 heterotetramers), which consists of two subunits, named GyrA and GyrB. The first subunit contains the breakage-reunion active site, and the second subunit promotes ATP hydrolysis. The GyrA is a clinically validated target of the fluoroquinolone antibiotics, such as moxifloxacin. In contrast, GyrB has been comparatively underexplored, presenting a promising avenue for combating fluoroquinolone-resistant TB.36,37 Therefore, inhibition of DNA gyrase impairs DNA replication and induces persistent double-strand breaks.
5.3. DnaN
DNA polymerase III sliding clamp (DnaN) is a key part of DNA polymerase III. Inhibition of DnaN disrupts its interaction with the polymerase III subunit (DnaE1), reducing replication processivity and causing DNA strand breaks [38]. DnaN is validated as a new anti-tuberculosis target, and is suggested to be a promiscuous target. Its inhibition interrupts essential polymerase and DNA repair activities, leading to the eradication of M. tuberculosis [39].
5.4. ATP Synthase
Adenosine Triphosphate Synthase (ATP Synthase) is a core enzyme in the synthesis of adenosine triphosphate (ATP). It generates the ATP molecule using proton motive force (PMF) and consists of two major regions, F0 and the F1 region. The F0 region is mostly hydrophobic and lies within the inner membrane of mitochondria, and the F1 region lies in the matrix of the mitochondria. The F0 and F1 are connected at two points and release ATP molecules into the mitochondrial lumen. The ATP is the principal source of energy for the growth and development of mycobacteria. Inhibiting ATP Synthase impairs energy metabolism and diminishes intracellular ATP levels in M. tuberculosis. Hence, ATP Synthase is a validated drug target for the identification of novel anti-TB drugs [40].
5.5. LeuRS
Leucyl-tRNA synthase (LeuRS) belongs to the class I aminoacyl-tRNA synthase subgroup and plays an important part in intracellular transport. Therefore, LeuRS is a promising target for anti-tuberculosis drugs to solve the problem of drug-resistant tuberculosis. Aminoacyl-tRNA synthetases are a family of essential enzymes that attaches the appropriate amino acid onto its corresponding tRNA in the process of protein synthesis. LeuRS has two catalytic sites: an aminoacylation site, which charges tRNALeu with leucine, and an editing or proof-reading site, which hydrolyses incorrectly charged tRNALeu [34]. Hence, current research is exploring LeuRS as a potential target for validating novel antibiotics against DR-TB.
5.6. QcrB
Cytochrome b subunit (QcrB) is an essential part of the cytochrome bc1 complex in M. tuberculosis. This complex is a key element of the respiratory enzyme machinery, facilitating electron transport within the electron transport chain (ETC) and driving ATP synthesis. Many heterocyclic compounds target the QcrB subunit of the cytochrome bcc complex, mainly at the Qp site. Inhibition of QcrB interrupts the ability to produce energy in M. tuberculosis [41].
5.7. DprE1
Decaprenylphosphoryl--D-ribose 20-epimerase 1 (DprE1) is a flavoprotein that works jointly with decaprenylphosphoryl-D-2-keto erythro pentose reductase (DprE2) to produce an arabinose precursor. The arabinose precursor is crucial for the synthesis of polysaccharides (arabinogalactan and lipoarabinomannan), which constitute the cell wall of M. tuberculosis [42]. In addition, DprE1 is an extra cytoplasmic protein and easily accessible for targeted drugs. Hence, inhibition of DprE1 blocks mycobacterial cell wall synthesis, leading to cell lysis and death [43].
5.8. FadD32 and Pks13
MAs are essential for survival, persistence, and virulence, contribute to the intrinsic resistance of M. tuberculosis. Therefore, inhibiting crucial enzymes such as fatty acid degradation protein D32 (FadD32) and polyketide synthase 13 (Pks13), which are involved in the biosynthesis of MAs, is considered a viable strategy in TB drug discovery [44]. FadD32 links the fatty acid synthase (FAS) system and polyketide synthase (PKS) pathways by transferring meromycolyl-AMP to Pks13. Then, Pks13 catalyses a condensation reaction, coupling both the FAS I-generated C26a-alkyl branch and FAS II-generated C40-60 meromycolate precursors, resulting in the assembly of a chain attached to trehalose, followed by a final reduction step to form trehalose monomycolate (TMM) that serves as a precursor for MAs.
These TMMs get transported from cytoplasm to periplasm via the mycobacterial membrane protein large 3 (MmpL3) [43]. Hence FadD32 and Pks13 are crucial to maintain the integrity of the outer membrane of M. tuberculosis. Therefore, the inhibition of FadD32 and Pks13 impairs the last steps of biosynthesis of mycolic acids, which are essential and specific lipids of mycobacteria, making them essential drug targets.
5.9. MmpL3
MmpL3 is an essential and required inner-membrane protein for the transport of TMMs through the cell membrane for cell-wall biosynthesis in M. tuberculosis. MmpL3 is crucial for the replication and viability of M. tuberculosis. The knock-out of MmpL3 results in the intracellular deposition of TMMs and a concurrent depletion of mycolates associated with the cell wall, a disruption that is bactericidal. Hence, MmpL3 has emerged as an important target for anti-tuberculosis drug discovery [46].
5.10. InhA
The NADH-dependent enoylacyl carrier protein (ACP) reductase (InhA) catalyses an essential step in fatty acid biosynthesis of M. tuberculosis. It is a key target of anti-tubercular drugs for combating MDR-TB [47]. Catalase-peroxidase (KatG) is required for activation of InhA. However, the high frequency of resistance-conferring mutations hinders its clinical utility, the requirement for activation by the catalase–peroxidase enzyme (KatG), and the wide interpersonal variation in human N-acetyltransferases, are responsible for drug metabolism [48,49].
5.11. MurI
Glutamate racemase (MurI) is a vital enzyme in phase I peptidoglycan (PG) biosynthesis of M. tuberculosis. MurI is a pyridoxal phosphate (PLP)-independent amino acid racemase that racemizes L-glutamate to D-glutamate, a building block of the MurNAc-linked and MurNGly-linked peptides of peptidoglycan. The well-known clinical value of other targets present in PG biosynthesis makes it an attractive drug target [48].
5.12. KasA
The kasA gene encodes a beta-ketoacyl-ACP synthase enzyme (KasA), which is crucial for the synthesis of mycolic acids. Whole-genome sequencing of resistant strains identified a single-nucleotide polymorphism (SNP) in the kasA gene as the vulnerable target. The reports indicate that in vitro growth of M. tuberculosis is highly dependent on KasA and the FAS-II pathway in general. The data supporting in vitro essentiality and vulnerability of kasA in M. tuberculosis have created a significant impetus to attain in vivo studies of this drug target [49].
5.13. Efflux pumps
Efflux pumps are membrane-bound proteins, actively expel a wide range of substances from bacterial cells and are essential in antimicrobial resistance by lowering intracellular drug concentrations. The efficacy of anti-TB drugs could be restored/made more effective by inhibiting the efflux pumps such as EfpA, Rv1819c, Mmr, and P55 (Rv1410c), among others [50,51]. Hence, Efflux pumps in M. tuberculosis are a substantial factor in drug resistance, making them a potent target for new anti-tuberculosis treatments.
5.14. PurF
Amidophosphoribosyltransferase (PurF) is the first enzyme in the de novo purine biosynthesis pathway, a critical metabolic route that M. tuberculosis uses to create purines (essential components of RNA and DNA). PurF catalyses the first and committed step of de novo, by transferring a nitrogen atom from glutamine to phosphoribosylpyrophosphate (PRPP) to form glutamate and phosphoribosylamine (PRA) [52]. Researchers aim to interrupt the bacterium's ability to produce vital building blocks for the creation of nucleic acids by targeting PurF, eventually hampering its survival [53].
Recently, β-ketoacyl-ACP-Synthase-I, biotin protein ligase, Leucyl-tRNA synthetase and tryptophan synthase have grabbed attention as novel anti-TB drug targets [38].
6. TB research and development
The rapid emergence and spread of drug-resistant M. tuberculosis strains pose a significant and growing challenge to achieving the goals of the WHO’s End TB Strategy. In particular, the threat of MDR-TB underscores the urgent need for advanced diagnostics, effective vaccines for adults, and innovative drug regimens tailored to resist forms of TB. Encouragingly, the TB diagnostic pipeline has seen notable expansion, including a broader array of diagnostic classes, test platforms, and methodologies in development. Among these, biomarker-based point-of-care and near point-of-care tests offer rapid and accessible diagnosis of active TB disease [1]. As of the latest updates, there are 15 vaccine candidates in clinical trials, four in Phase I, five in Phase II, and six in Phase III. In the current TB drug pipeline, there are 29 anti-TB drug candidates in various stages of clinical development: Phase I, Phase II, and Phase III trials. Additionally, around 30 clinical trials are actively ongoing worldwide, and implementation of research studies is underway to evaluate new drug regimens and models of delivery for TB preventive treatment [1].
The TB drug discovery and development includes two approaches for hit identification: the first is target-based screening against a particular essential enzyme, and the second is phenotypic screening involving screening against wild-type or recombinant whole- M. tuberculosis cells [36,43]. The whole-cell screening followed by elucidation of MoA has been the most effective approach in progressing novel drug-like compounds into the TB drug discovery pipeline (https://www.newtbdrugs.org/pipeline/discovery) [15].
7. Current TB Drug Pipeline
In the development of new TB drugs, there are several classes of drug candidates have shown in Table 1, such as diarylquinoline (Bedaquiline, TBAJ-876 and Sudapyridine (Pyridine ethanol analog of bedaquiline), nitroimidazole (delamanid and petromanid) oxazolidinones (sutezolid, delpazolid, Tedizolid, TBD09, and OTB-658), imidazopyridine amide (telacebec), Amido piperidine (Alpibectir) Benzothiazinone (BTZ-043 and Macozinone), beta-lactum (Sanfetrinem), Riminophenazines (TBI-166), 3,4-Dihydrocarbostyril (OPC-167832), Azaindole (TBA-7371), Oxaborole (GSK-656), Pyrimidine (GSK-286) and Tetrazole (GSK-839), etc. are in the current TB drug pipeline (Figure 5) [54].
Figure 5. Current clinical-development pipeline for anti-TB drugs and regimens, November 2024. *new chemical class; OBR, optimized background regimen. (Adapted with permission from the Stop TB Partnership Working Group on New Drugs pipeline; for detailed information, please see: http://www.newtbdrugs.org.)
Illustrations are not included in the reading sample
Each of these novel TB drug candidates is being developed to shorten the treatment of drug-sensitive TB (from 6 months to 4 months) and to substitute isoniazid or ethambutol. From the present clinical pipeline, drugs in the earlier stages exhibit greater target diversity relative to those in advanced stages – a reflection of the recently renewed interest in TB drug development.
TABLE 1 Details of drug candidates in the current TB drug pipeline
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However, inhibition of cell wall synthesis and protein translation is well represented across the pipeline. Hence, focusing on compounds with orthogonal mechanisms of action is a strategic approach in TB drug development that aims to minimise the risk of cross-resistance and enhance treatment efficacy. Here are some drug candidates in various stages of development that exhibit unique mechanisms.
In the past decade, only three new drugs˗Bedaquiline, Delamanid, and Petromanid have received regulatory approval for TB treatment and have been incorporated into regimens for DR-TB. These are the first anti-TB drugs with novel mechanisms of action to enter the market in over 50 years, highlighting the high attrition rates in anti-TB drug development and approval [2,55]. The novel class of TB drugs, which are being evaluated in human trials, are detailed below, and their structures are depicted in Figure 6 (Compounds in Phase 2 & 3 trials) & Figure 7 (Compounds in Phase 1 and early stage development).
Figure 6. Anti-TB drugs/drug candidates in Phase 2 & 3 trials
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Figure 7. Anti-TB drug candidates in Phase 1 and early-stage development
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8. Novel chemical classes in the CURRENT TB Drug pipeline
After decades of limited progress, a growing pipeline of novel compounds and compound classes is being developed for their effectiveness in TB treatment. Although some compounds, such as rifapentine, diarylquinolines, fall within drug classes already approved for the treatment of TB, most belong to novel chemical classes that have not yet been authorised for TB therapy. Within this group, several chemical classes have been approved for the treatment of other bacterial infections, including the nitroimidazoles, fluoroquinolones, oxazolidinones, and macrolides. There are also novel chemical entities that have never been approved for use in humans, including the pyrimidines, imidazopyridines, aminopiperidines, azaindoles and oxaboroles.
8.1. Diarylquinolines
Bedaquiline acts by inhibiting mycobacterial ATP synthase, and must be prescribed and taken by patients who develop resistance towards the main TB drugs, isoniazid and rifampicin [56-58]. The United States Food and Drug Administration (USFDA) approved paediatric formulation of bedaquiline (with brand name Sirturo, Janssen Pharmaceuticals) for use in combination therapy for pulmonary MDR‑TB in patients ≥ 5 years of age, including adults [55,56]. More recently, Sirturo received traditional drug status for TB Treatment from the FDA [59].
Recently, Bedaquiline use has been linked to adverse effects, notably an elevated risk of unexplained mortality, QTc prolongation, and hepatotoxicity that limits its wide clinical use. Based on Bedaquiline, a Pyridine ethanol analogue of Bedaquiline named Sudapyridine (WX-081) has been developed. It exhibited excellent anti-mycobacterial activity with low cytotoxicity, better lung exposure, and lower QTc prolongation potential compared to Bedaquiline [60,61]. Currently, Sudapyridine is under clinical Phase III development [62].
TBAJ-876 [63] and TBAJ-587 [64,65] are also novel diarylquinolines developed by TB Alliance, and are more effective with a small predicted clinical dose, suggesting potential for improved tolerability compared to Bedaquiline [66,67]. TBAJ-876 is undergoing a Pan-Phase 2 clinical trial (combining components of Phase 2a, 2b, and 2c), while TBAJ-587 is currently in a Phase 1 clinical trial [63,64].
8.2. Nitroimidazoles
Delamanid (formerly OPC-67683) belongs to a novel class of drugs called nitroimidazoles, used for TB with a trade name of Deltyba and developed by the Otsuka Pharmaceutical company [68,69]. It poisons cells by liberating reactive nitrogen species (RNS) and blocks cell wall synthesis and is indicated for use in combination therapy along with standard agents, not as monotherapy. Generally, it is prescribed for patients diagnosed with XRD-TB [70-72]. Pretomanid (formerly PA-824) is another nitroimidazole-class drug developed by the TB Alliance, which is included in new TB drug regimens and is effective for both drug-sensitive and DR-TB affecting the lungs. In August 2019, it received FDA authorisation for use in combination with Linezolid and Bedaquiline (referred to as the BPaL regimen) and BpaLM regimen for people atleast 14 years old, with non-responsive or treatment-intolerant RR-TB, MDR-TB or XDR-TB [72,73]. Pretomanid was studied over 109 participants across South Africa (three sites) as part of the Nix-TB trial [74].
8.3. Rifamycin
Sanofi-Aventis developed one more drug candidate, Rifapentine, with the trade name Priftin, for TB treatment. It was identified through optimization of the lead compound, Rifamycin, and acts as an inhibitor of DNA-dependent RNA polymerase specifically in bacteria but not in the mammalian enzyme. Priftin is used to treat drug-susceptible TB and is undergoing a Phase 2 trial with other drug combinations to shorten the treatment duration [75].
8.4. Fluoroquinolines
The fluoroquinoline class of drugs, Ofloxacin and Levofloxacin, are being used as second-line TB drugs. Fluoroquinoles such as Moxifloxacin and Gatifloxacin from the same class are also being developed to reduce the treatment regimen [66]. Currently, Moxifloxacin is part of many clinical studies, developed by Bayer and the TB Alliance [76,77].
8.5. Oxazolidinones
Linezolid is an oxazolidinone used in the treatment of MDR-TB, and is associated with adverse effects such as anaemia, optic neuropathy and peripheral neuropathy, etc. New candidates from the same family named Sutezolid (formerly PNU-100480) [78], Delpazolid (formerly LCB01-0371) [79] and Tedizolid [80] have been developed by Sequella with TB Alliance, LegoChem Biosciences, Inc. and Cubist Pharmaceuticals & Trius Therapeutics, respectively. Generally, oxazolidinones act on M. tuberculosis by inhibiting protein synthesis through binding to the 50S/23S ribosomal subunit [81].
Sutezolid is a thiomorpholinyl analogue of Linezolid, significantly reducing the number of colony-forming units that act by binding to the 23S rRNA of the bacterial ribosome. Now, it is being studied in Phase II, and Phase IV trials [78]. Delpazolid (LCB01-0371) is a novel oxazolidinone compound featuring a cyclic amidrazone moiety. Delpazolid in combination with Bedaquiline, Delamanid, and Moxifloxacin was evaluated for safety, efficacy, and tolerability in patients with pulmonary TB for Phase II clinical studies [82,83]. These novel oxazolidinones have demonstrated strong activity against resistant forms of M. tuberculosis in preliminary tests and are currently in Phase 2 clinical trials [54]. In addition, novel oxazolidines such as TBD09 (MK-7762), TBI-223, and OTB-658 are being developed to act on drug-resistant M. tuberculosis strains and are now in Phase 1 and preclinical trials [84].
8.6. Imidazopyridine amide
Telacebec (Q203) is a molecule that belongs to the Imidazopyridine amide class and acts by selective inhibition of the cytochrome bc1 complex of M. tuberculosis. Telacebec was identified as a strong drug candidate under Phase 2a clinical evaluation for drug-susceptible TB (DS-TB) & DR-TB. It is a first-in-class, safe, and well-tolerated drug with variations in dose strengths. It has good results in Phase 2a, entered late-stage trials [85,86].
8.7. Amidopiperidine
Alpibectir (BVL-GSK098) belongs to the class of amido piperidine, developed jointly by BioVersys AG and GlaxoSmithKline. It acts via a new mechanism on bacterial transcriptional regulators, stimulating novel bioactivation pathways for Ethionamide (Eto) /Protionamide (Pto) (Second-line TB drugs with negative effects such as gastrointestinal intolerance, and hepatotoxicity), resulting in an improved efficacy of Eto/Pto, while in chorus overcoming resistance to Eto/Pto [87]. The combination of BVL-GSK098 and low-dose Eto/Pto would allow for a safer and better-tolerated dose of Eto/Pto, which could result in making Eto/Pto a valuable treatment for XDR- and MDR-TB treatment. Moreover, it opens the opportunity for the use of Eto/Pto to be considered as a first-line therapy against M. tuberculosis, replacing Isoniazid. Hence, BVL-GSK098 will be the first example to be assessed in interventional studies with a new kind of action (targeting bacterial transcriptional regulators) for bacterial infections [88]. Recently, Alpibectir and Eto fixed-dose combination received the USFDA orphan-drug designation for the treatment of tuberculosis [89].
8.8. Benzothiazinones
BTZ-043 is a new TB drug that belongs to the class of Benzothiazinone and acts by inhibiting cell wall synthesis through blocking DprE1 of M. tuberculosis [90,91]. BTZ-043 is active against all tested M. tuberculosis strains, including clinical isolates of MDR and XDR strains, and is currently being entered into Phase 2 clinical trials [92]. From the lead BTZ043, Macozinone (PBTZ-169) has been developed with lower cytotoxicity and improved efficacy in a murine model than BTZ-043. The Phase I clinical trial of Macozinone is being conducted by iM4TB (Innovative Medicines for Tuberculosis) and the Bill & Melinda Gates Foundation [93].
8.9. 3,4-Dihydrocarbostyril
A new potential drug candidate, Quabodepistat (OPC-167832), a derivative of carbostyril, developed by Otsuka Pharmaceuticals, exhibits excellent activity and has the potential to reduce the treatment duration and achieve better outcomes [94]. It acts by inhibiting DprE1, which ends the formation of a key precursor for the synthesis of arabinans on the M. tuberculosis cell wall [95]. Early results suggest that regimens with OPC-167832 and Delamanid, at the core, could potentially curtail treatment duration and improve treatment outcomes.
Interim data from a Phase 2b/c trial exploring OPC-167832, in combination with bedaquiline and delamanid, for the treatment of pulmonary tuberculosis (TB) is encouraging and capable of shortening the TB treatment duration. Hence, it received fast-track status from the USFDA, and human trials are in progress [94]. Currently, Quabodepistat is a part of the novel Pan-TB regimen along with Delamanid and other new anti-TB drugs to shorten the TB treatment [96].
8.10. Azaindoles
TBA-7371 is a compound with an azaindole heterocycle, which has shown potent activity against M. tuberculosis (MIC range of 0.78–3.12 μM). TBA-7371 is a noncovalent DprE1 inhibitor that has completed a Phase I clinical trial and exhibits efficacy in a rodent model of tuberculosis. It is being developed by TB Alliance, Bill & Melinda Gates Medical Research Institute, and Foundation for Neglected Diseases Research. From the preliminary studies, TBA-7371 could shorten the standard therapy course and has no cross-resistance to the current anti-TB drugs [81,97]. A Phase II clinical trial of TBA-7371 is recruiting participants to test early bactericidal activity, safety, and pharmacokinetics currently [98,99].
8.11. Trinem beta-lactums
Sanfetrinem is a novel tricyclic carbapenem that exhibits strong and rapid bactericidal activity against intracellular M. tuberculosis. Sanfetrinem cilexetil (Pro-drug of Sanfetrinem) was developed by GlaxoSmithKline in the 1990s, underwent Phase 2 clinical trials for upper respiratory infections, and a Phase 3 clinical trial was halted mainly based on commercial considerations [100]. Now, it has been repurposed for TB cure and is undergoing Phase 2a clinical evaluation [101].
8.12. Ethylenediamines
SQ109 is an ethylene diamine antibiotic, found to be safe and well-tolerated in pulmonary drug-sensitive and MDR-TB patients, and is being developed by Sequella and Infectex [102]. The SQ109 has a triple mode of action that includes (i) inhibition of MmpL3, (ii) inhibition of the enzymes MenA and MenG, which are involved in menaquinone biosynthesis, and (iii) the reduction of ATP synthesis acting as an uncoupler [103]. Hence, SQ109, with its three unique mechanisms of action, is divergent from other drugs used in the TB regimen. SQ109 is in Phase 2 clinical trial studies in drug-sensitive TB patients in Africa and the Phase 2b-3 study in Russia presently [104].
8.13. Riminophenazines
TBI-166 shows more potent anti-TB activity than clofazimine, while both originate from a riminophenazine analogue [105]. TBI-166 was identified through a lead optimization effort by TB Alliance and the Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing. It has shown better physicochemical and pharmacokinetic properties, will avoid discolouration of the skin, but fight TB with more efficacy than clofazimine [106]. TBI-166 acts by significantly increasing bacterial reactive oxygen species (ROS), and is being evaluated against M. tuberculosis in a Phase 2a clinical trial [107].
8.14. Oxaboroles
Ganfeborole (GSK-656), a novel 3-aminomethyl-4-chloro-benzoxaborole, exerts anti-TB effects by inhibiting LeuRS, one of 20 aminoacyl-tRNA synthetases, which plays a crucial role in the protein synthesis of M. Tuberculosis. Ganfeborole binds to the catalytic site of LeuRS, is responsible for the hydrolysis of incorrectly ligated aminoacylated tRNAs [108,109]. Recently, to evaluate the early bactericidal activity, safety, and tolerability of GSK3036656 in TB patients, a Phase 2a clinical trial was conducted by GlaxoSmithKline. Ganfeborole was well tolerated with no serious adverse events identified in the evaluation [110,111].
8.15. Pyrimidines
GSK 2556286 (GSK-286) is a new chemical entity with a new mode of action related to cholesterol catabolism. It is a substituted 4-aryloxypiperidine and a novel anti-TB drug candidate, effective against both MDR-TB/XDR-TB and DS-TB strains [112]. GSK-286 inhibits adenylyl cyclase, an enzyme essential for Cholesterol Catabolism in M. tuberculosis, by which the current TB treatment can potentially be shortened [113,114]. A first-time-in-humans (FTIH) trial for GSK-286 was begun in 2020 and stopped based on pre-defined stopping criteria in the protocol as the enrolments are 92/96 in 2025 [115].
8.16. Tetrazoles
GSK839 is a new chemical class of drug that contains a tetrazole ring and is a preclinical candidate for Tuberculosis treatment. GSK839 is first-in-class with a novel mechanism of action through a selective inhibition of Tryptophan Synthase (TrpAB). GLP toxicity studies are ongoing for GSK839 by GlaxoSmithKline [116].
8.17. Pyrrolidinopyrimidines
JNJ-6640 is a new lead candidate that belongs to the class of Pyrrolidinopyrimidines and is a first-in-class small-molecule inhibitor targeting PurF. It exhibited nanomolar bactericidal activity in vitro and showed high selectivity towards mycobacterial PurF. Identification of JNJ-6640 as a PurF inhibitor validates a novel metabolic target and marks a significant advancement in TB drug discovery [53].
Several new classes of compounds are currently in early-stage development for the treatment of TB (Figure 7). The completely new regimens may ease and shorten the treatment duration for all types of TB to reach the target ‘End TB 2030’.
9. Conclusion
Although TB is preventable and curable, it remains the deadliest infectious disease globally, driven by the emergence of drug resistance and various risk factors that complicate current treatment options. Drug resistance poses one of the most critical public health threats, often leading to lengthy treatment regimens with limited success and severe toxicity. This is especially true for XDR-TB, which is associated with alarmingly high mortality rates and severely restricted treatment options. There is an urgent need for faster-acting and shorter TB drug regimens. In recent years, collaborative efforts across diverse research fields have expanded the TB drug discovery and development pipeline, resulting in the regulatory approval of Bedaquiline (Diarylquinoline), Delamanid, and Petromanid (both Nitroimidazoles) for the treatment of DR-TB and MDR-TB. However, this progress is incomplete, and there remains a pressing need for novel drug combinations to treat XDR-TB effectively and combat emerging resistance.
A robust pipeline of new compounds in preclinical and clinical development aims to strengthen our arsenal against DR-TB and DS-TB, offering potential for shorter, more effective regimens with reduced toxicity. These challenges underscore the need for a new class of TB compounds with novel modes of action to advance drug design and discovery efforts. Hence, this book outlines the emergence of drug resistance, current insights into the pathogen’s biology, and the novel chemical entities presently in the TB drug pipeline.
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