Move over COVID, Tuberculosis Is Once again the Leading Cause of Death from a Single Infectious Disease

InfoMetricsFiguresRef. Journal of Medicinal ChemistryASAPArticle This publication is free to access through this site. Learn More CiteCitationCitation and abstractCitation and referencesMore citation options ShareShare onFacebookX (Twitter)WeChatLinkedInRedditEmailJump toExpandCollapse EditorialDecember 9, 2024Move over COVID, Tuberculosis Is Once again the Leading Cause of Death from a Single Infectious DiseaseClick to copy article linkArticle link copied!Tomayo BeridaTomayo BeridaWarren Center for Neuroscience Drug Discovery and Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United StatesMore by Tomayo Beridahttps://orcid.org/0000-0002-3578-1033Craig W. Lindsley*Craig W. LindsleyWarren Center for Neuroscience Drug Discovery and Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States*Tomayo Beridahttps://orcid.org/0000-0002-3578-1033 and Craig W. Lindsley, Editor-in-Chief, J. Med. Chem. https://orcid.org/0000-0003-0168-1445, [email protected]More by Craig W. Lindsleyhttps://orcid.org/0000-0003-0168-1445Open PDFJournal of Medicinal ChemistryCite this: J. Med. Chem. 2024, XXXX, XXX, XXX-XXXClick to copy citationCitation copied!https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c02876https://doi.org/10.1021/acs.jmedchem.4c02876Published December 9, 2024 Publication History Received 22 November 2024Published online 9 December 2024editorialPublished 2024 by American Chemical Society. This publication is available under these Terms of Use. Request reuse permissionsThis publication is licensed for personal use by The American Chemical Society. ACS PublicationsPublished 2024 by American Chemical SocietySubjectswhat are subjectsArticle subjects are automatically applied from the ACS Subject Taxonomy and describe the scientific concepts and themes of the article.Antimicrobial agentsCellsDrug resistanceInfectious diseasesPharmaceuticalsTuberculosis (TB), an airborne infection caused by the disease Mycobacterium tuberculosis (Mtb), has plagued mankind for millennia. Between the 1600–1800s, TB was responsible for 25% of the deaths in Europe and the United States. Today, with over 1 million deaths annually, TB has earned a reputation as the leading cause of death from a single infectious disease─a position briefly challenged by COVID-19 from 2020 to 2021. (1,2) If anything, the remarkable increase in the number of new infections reported by the World Health Organization (WHO) in the recent Global Tuberculosis Report 2024 has only reinforced the reputation of TB as the deadliest infectious disease in recorded history. (1) According to the report, 10.8 million people contracted TB and about 1.25 million died from the disease in 2023. Most of these new cases occurred in 30 heavily burdened countries, of which five countries (India, Indonesia, China, the Philippines, and Pakistan) account for 56% of the cases. (1) A fourth of the world's population is believed to be infected with the latent form of the disease, and 13 million of these people reside in the United States. There is a 5% risk that these individuals will develop the active disease, but this risk is significantly higher for individuals with a compromised immune system. For instance, HIV-positive patients face an 18-fold higher likelihood of developing TB than those with intact immune function. Although TB is treatable, challenges like poverty, drug misuse, and human-to-human transmission continue to drive the rapid emergence and spread of drug resistance worldwide. The current arsenal of TB treatments, combined with the slow pace of new drug discovery, is insufficient to effectively combat rising resistance, particularly in multidrug-resistant (MDR) TB forms. Hence, there is an urgent need to accelerate TB drug development.TB Drug and Mtb ResistanceClick to copy section linkSection link copied!Active TB is routinely treated with a combination of four first-line drugs that include rifampicin (RIF), isoniazid (INH), ethambutol (EMB), and pyrazinamide (PZA) in 4- or 6-month courses of treatment (Figure 1). (3) Sadly, the misuse of antimicrobial drugs and person-to-person transmission are accelerating the rise and spread of drug-resistant TB (DR-TB) globally. (2) The increasing prevalence of RIF-resistant (RR)-TB and multidrug-resistant TB (MDR-TB)─caused by Mtb strains resistant to both isoniazid (INH) and rifampicin (RIF)─is a major global health threat. Furthermore, resistance to second-line drugs has led to pre-extensively drug-resistant TB (pre-XDR-TB) and extensively drug-resistant TB (XDR-TB). The WHO defines pre-XDR-TB as TB stemming from MDR-TB strains that are resistant to fluoroquinolones such as levofloxacin or moxifloxacin. XDR-TB meets the criteria for pre-XDR-TB but has additional resistance to at least one of bedaquiline or linezolid. (2,4) In 2023, an estimated 400,000 people developed MDR/RR-TB. The treatment success rate for these drug-resistant cases was 68% compared to 88% for drug-susceptible TB. Diagnosis and treatment of TB places a grave financial burden on the patients, their families, and the government. DR-TB further escalates these costs, often consuming more than half of the TB budgets while representing less than 10% of total TB cases. (5)Figure 1Figure 1. Antitubercular drugs in clinical use. (3,4)High Resolution ImageDownload MS PowerPoint SlideThe threat TB poses to global health security demands a holistic, global response from scientists, affected communities, governments, and society at large. On September 22, 2023, United Nations Member States adopted a political declaration reiterating their commitment to eradicating TB by 2030. (6) The declaration called for innovative and effective approaches to address all forms of TB, including DR strains. More recently, on May 22, 2024, the UN released a zero draft of the Political Declaration on Antimicrobial Resistance (AMR), outlining strategies to combat DR, including MDR-TB, worldwide. In actualizing the 'End TB Strategy', medicinal chemists are crucial in offering innovative scientific solutions and collaborating with stakeholders to translate these successes into TB patient care. Medicinal chemists must therefore be equipped with a firm understanding of both the scientific challenges and the social-political hurdles that must be overcome to achieve a decisive victory against TB.Mechanisms of Acquired ResistanceClick to copy section linkSection link copied!Drug resistance in Mtb primarily arises from genetic mutations, especially single nucleotide polymorphisms, which are then spread through the replication of resistant strains and human-to-human transmission. (2) Resistant mutations are usually associated with genes coding for drug targets, the enzymes that activate prodrugs, efflux pumps, or a combination of these. RIF resistance, for instance, is acquired through mutation in the rpoB gene, which encodes the β-subunit of RNA polymerase, the molecular target of RIF. Clinically, resistance to bedaquiline has been linked to mutations in the mmpR5 gene, which regulates the MmpS5-MmpL5 efflux system that can expel bedaquiline from the bacilli. (7) Other mutations in genes such as atpE, mmpR5 [Rv0678], mmpS5, mmpL5, pepQ, and Rv1979c have also been identified as the cause for bedaquiline resistance through in vitro and in vivo models. (8) Recent evidence suggests that epigenetic mechanisms, such as DNA methylation, histone modifications, and various RNA-based processes, may play a role in promoting resistance to several anti-TB agents. (9−12) These epigenetic mechanisms cause transferable phenotypic changes in organisms without changing the DNA sequence itself. (13) For example, it has been shown that methyltransferases (e.g., HsdM) decrease the susceptibility of bacteria to isoniazid (INH). (14,15) The TB Pipeline, Restocking the ArsenalWith antimicrobial resistance advancing faster than TB drugs are approved, restocking the anti-TB armamentarium is urgently needed to outpace resistance. Each year, the WHO publishes an extensive analysis of antimicrobial agents in clinical and preclinical development, serving as an essential resource for medicinal chemists in antimicrobial research. In its 2023 report, 19 compounds were identified at the clinical stage, while 43 were in preclinical stages (Table 1 and figure). (16,17) The WHO evaluates antibiotics, both approved and in development, based on four key innovation criteria: new chemical class, novel target, unique mechanism of action, and absence of cross-resistance. (16) Of the 19 compounds in the clinical stage, only 6 meet the criterion of no known cross-resistance, while 11 satisfy at least one of the innovation criteria. Ganfeborole (GSK3036656), a leucyl-tRNA synthetase (LeuRS) inhibitor, meets all four WHO innovation criteria and is notable as the first boron-based anti-TB candidate in clinical development (Table 1, Figure 2). Through a mechanism called oxaborole tRNA-trapping (OBORT), it prevents leucylation by forming a stable adduct with the terminal nucleotide of tRNALeu, thus inhibiting protein synthesis. (18) Ganfeborole shows potent activity against Mtb H37Rv (MIC = 0.08 μM) with high selectivity for Mtb LeuRS (IC50 = 0.20 μM) over human cytoplasmic (IC50 = 132 μM) and mitochondrial (IC50 = 300 μM) LeuRS. (19,20)Table 1. Current clinical pipeline of antitubercular drugsa Chemical class Innovation CriteriaName(Target)DeveloperNCRNCCNTMoAPhase ITBI-223OxazolidinoneTB Alliance/Institute of Materia Medica××××GSK2556286 (GSK286)Adenylyl cyclase Rv1625c agonistGSK/TB Drug Accelerator/Gates MRI?√√√Macozinone (PBTZ-169)Benzothiazinone (DprE1 inhibitorInnovative Medicines for Tuberculosis/Nearmedic Plus√√√√TBAJ-587Diarylquinoline (bedaquiline analogue)TB Alliance××××TBD09 (MK7762)OxazolidinoneGates MRI××××Phase IIBTZ-043Benzothiazinone (DprE1 inhibitor)University of Munich/Hans Knöll Institute, Jena/German Center for Infection Research√√√√Delpazolid (RMW2001, LCB01-0371)OxazolidinoneLegoChem Biosciences/Haihe Biopharma××××Ganfeborole, GSK3036656 (GSK070)Oxaborole (LeuRs inhibitor)GSK√√√√Sutezolid (PF-2341272, PNU-100480)OxazolidinoneTB Alliance/Sequella/Gates MRI/Aurum Institute××××TBA-7371Azaindole (DprE1 inhibitor)TB Alliance/Gates MRI/Foundation for Neglected Diseases Research√√√√Telacebec (Q203)Imidazopyridine amideQurient/Infectex/TB Alliance√√√√Quabodepistat (OPC-167832)3,4-Dihydrocarbostyril (DprE1 inhibitor)Otsuka/Gates MRI√√√√TBAJ-876Diarylquinoline (bedaquiline analogue)TB Alliance××××Pyrifazimine (TBI-166)Riminophenazine (clofazimine analogue)Institute of Materia Medica/TB Alliance/Chinese Academy of Medical Sciences/Peking Union Medical College××××Alpibectir (BVL-GSK098) + ethionamideAmido piperidine (inactivation of TetRlike repressor EthR2) spiroisoxazolineBioVersys/GSK×√××Dovramilast (CC-11050, AMR 634)PDE4 inhibitor (host immune response)Medicines Development for Global Health×√××SQ109EthylenediamineSequella?-√√Sanfetrinem cilexetilTricyclic β-lactamGSK/Gates MRI××××Phase IIISudapyridine (WX-081)Mycobacterial ATP synthase inhibitionShanghai Jiatan Biotech××××aTable one was adapted from WHO's 2023 Antibacterial agents in clinical and preclinical development. (16) NCR: No cross resistance, NCC: New chemical class; NT: New target; MoA: New mechanism of Action.Figure 2Figure 2. Antitubercular agent in clinical development.High Resolution ImageDownload MS PowerPoint SlideSQ109 is a novel ethylenediamine developed by Sequella that targets MmpL3, the mycolic acid transporter needed for the building of the Mtb cell wall (Figure 2). The compound was tested for effectiveness in two Phase 2 trials involving drug-sensitive TB patients in Africa, as well as in a combined Phase 2b–3 trial in Russia. (17) DprE1 inhibitors, including BTZ-043, PBTZ-169, TBA-7371, and Quabodepistat (OPC-16832), are well-represented in clinical development (Table 1, Figure 2). These inhibitors target DprE1, a crucial enzyme in Mtb cell wall synthesis, and disrupt cell wall production by binding to DprE1 either covalently or noncovalently, impairing the synthesis of cell wall arabinan. Dovramilast (CC-11050, AMR-634) does not directly target Mtb but instead suppresses the immunopathological response to TB by selectively inhibiting Phosphodiesterase 4 (PDE-4). The compound has recently completed Phase 2a clinical trials for TB (NCT02968927). (17) Resources to monitor TB drug development include the WHO's recently launched TB Trial Tracker site (https://tbtrialtrack.who.int/#/), which provides updates on TB drug and vaccine advancements. Additionally, the Working Group on New TB Drugs offers an updated anti-TB pipeline overview (https://www.newtbdrugs.org/pipeline/clinical), an invaluable resource for medicinal chemists involved in TB drug development. Challenges and Opportunities in the Development of New Antitubercular Agents The Mycobacterium Cell Wall, a Defense Difficult to BreachMtb has coevolved with humans over thousands of years and has adopted numerous strategies to persist within the granuloma and evade the immune system. To a large degree, the difficulty of treating Mtb is due to its thick, lipophilic cell wall, which plays an essential role in its intrinsic resistance to antimicrobials (Figure 3). (21) This cell wall impedes drug penetration and possesses efflux pumps that continuously pump out antimicrobials from the cell. The cell wall is also implicated in various virulence strategies and, importantly, in Mtb's survival within the macrophage, where it can persist for decades, manipulating the immune system to its advantage. (22) Mycobacteria have cell envelopes rich in mycolic acids (MAs)─long-chain fatty acids that confer waxy characteristics to the cell structure. Unlike the cell walls of Mtb, Gram-positive and Gram-negative bacteria lack both the MA and arabinogalactan layers. Instead, they generally possess either significantly thicker or thinner peptidoglycan layers, respectively (Figure 3). (21)Figure 3Figure 3. Cell wall of mycobacteria (left), Gram-positive bacteria (center), and Gram-negative bacteria (right). The figure was adapted from "Plant Antibacterials: The Challenges and Opportunities", Berida et al, Heliyon 2024, 10 (10), e31145, with permission from Elsevier. (26)High Resolution ImageDownload MS PowerPoint SlideThe uniqueness of the TB cell wall has several implications relevant for drug discovery scientists. The most obvious is the challenge of designing a drug that can penetrate the cell wall and evade the efflux pumps within Mtb, allowing the drug to accumulate inside the cell. On the other hand, targeting the unique proteins or pathways essential for cell wall synthesis presents a strategy to selectively kill or inhibit Mtb growth. Narrow-spectrum agents are valued for their ability to preserve the essential human microbiome during treatment. Furthermore, narrow-spectrum antibacterials are desirable because they reduce the likelihood that other bacteria exposed to the antibiotic will develop resistance during prolonged TB treatment. Examples of narrow-spectrum agents targeting the Mtb cell wall include SQ109, which inhibits the mycobacterial membrane protein large 3 (MmpL3), an MA transporter. Additionally, DprE1 inhibitors such as BTZ-043 and Quabodepistat (OPC-16832) block the synthesis of arabinogalactan, a crucial component in Mtb cell wall biosynthesis. (23) The Need for Better InnovationGiven the classes of antibiotics approved since 2000 and the fact that the current antimicrobial pipeline is largely populated by modified chemotypes of existing TB drugs or agents targeting known mechanisms, concerns about a lack of innovation in TB drug R&D seem warranted. As it stands, there are no more 'low-hanging fruits' in antimicrobial drug discovery. These challenges present an opportunity for medicinal chemists to leverage recent advances in synthetic methodologies and state-of-the-art drug discovery tools to develop novel biologically active molecules. For example, recent advances in molecular editing offer opportunities to enhance biological activity and pharmacokinetic properties of drug candidates, as well as to generate entirely new classes of compounds. A notable example is the SmI2-catalyzed multiatom editing developed by Agasti et al., which enables the insertion of alkenes into bicyclo[1.1.0]butane, forming bicyclo[2.1.1]hexanes (BCHs), a bicyclic bioisostere of benzene. This method facilitated the expedient synthesis of a phthalylsulfathiazole analogue in which the ortho-disubstituted benzene ring in the broad-spectrum antibiotic is replaced with a bicyclo[2.1.1]hexane (BCH) ring, offering a novel chemotype. (24) Another example is the single-atom editing of fidaxomicin, a natural product (NP) approved for treating Clostridioides difficile infections. Replacing the O-glycosidic bond of fidaxomicin with an S-glycosidic bond led to improved acid stability and retention of biological activity under acidic conditions. (25)Nature─our source of some of the most potent antimicrobials─also has much to offer. Leveraging our current understanding of biosynthetic gene clusters (BCGs), heterologous expression, and bioinformatics tools, the potential for engineering specific metabolic pathways in plants and microorganisms to generate novel NPs with anti-TB activity continues to grow. (26,27) Moreover, the development of novel tools and methods to access hidden natural products, which have previously been inaccessible due to the inability of source organisms to grow or express the encoded compounds under standard laboratory conditions, is both revolutionary and promising. (27) A good example is the discovery of the novel tetracycline derivative isoindolinomycin from Streptomyces sp. by activating its cryptic gene clusters. (28)Other, more "non-traditional" drug discovery strategies could also prove fruitful for TB drug development, including targeted protein degraders, CRISPR-Cas-9, epigenetic therapies, microbiome-modifying, immunomodulators, antibody-recruiting molecules (ARMs), and antibody drug conjugates (ADCs). Proteolysis-targeting chimeras (PROTACs) are currently the most studied and promising class of targeted protein degraders. PROTACs are bifunctional molecules that link an E3 ubiquitin ligase to protein of interest (POI), bringing the two into proximity to promote the ubiquitination and subsequent degradation of POI by eukaryotic proteasome. (29) In mycobacteria, the ubiquitin-proteasome system is replaced by ClpCP proteolytic complexes. The recent discovery of BacPROTACs targeting ClpC1 of Mtb for degradation has heightened optimism for using targeted protein degradation to combat MDR-TB. (30) The Homo-BacPROTACs developed by Junk et al. were not only selective for mycobacteria but also effective against various drug-resistant Mtb strains (rifampicin, isoniazid, moxifloxacin) and showed activity against Mtb within macrophages. (31) Bringing in More Funds and the Big Pharmaceutical FirmsNot everyone agrees that innovation is the major problem of antimicrobial R&D. In 2024, Butler et al. argue that lack of financial and structural resources are bigger problems. (32) The average cost of taking a drug to the clinic is about $2 billion, a number far beyond the reach of most academic laboratories and small privately funded pharmaceutical companies that now dominate the antimicrobial preclinical space (TB pipe WHO). (33)According to the report published by Treatment Action Group, the total spending on TB research (including vaccine and diagnostics) between 2018 and 2022 reached $4.7 billion, covering only 37% of the $12.8 billion funding target set by the 2018–2022 Global Plan to End TB. (34) We can only hope that the global target of $5 billion in yearly TB R&D spending, set for 2027 at the second UN high-level meeting on TB, will be attainable. While we acknowledge the contributions of various governments, philanthropies (e.g., the Gates Foundation and the Wellcome Trust), private-sector companies, and multilateral organizations in funding current R&D efforts, it is crucial to recognize that additional financial resources are needed.Government and policy makers must act with greater urgency to set up strategies to ramp up funding and other resources for antimicrobial drug discovery. Such efforts must include policies to attract big and resource-rich pharmaceutical companies into the TB war. Most antibacterials used in clinical practice today are relatively inexpensive, and the majority are generics. Moreover, the relatively short duration of antimicrobial therapies and the limited prescription of antibiotics due to resistance concerns make sales-based profit models unreliable. As a result, the antimicrobial space continues to lose appeal for large pharmaceutical companies, further discouraging significant investment despite the protection offered by intellectual property (patent) rights. (35) Special financial incentives like tax credits and subsidies could be considered for companies working on anti-TB agents. Recently, the NHS in the UK began using the 'Netflix' subscription model for antibiotics prescribed for BPPL infections. This model provides some "pull incentive" that provides some financial guarantee for pharmaceutical companies working within the risky antimicrobial space. (36) Whether this model will be effective for TB, particularly in high-burden, low-income countries, is unclear. The Anti-TB CoalitionsWinning the war against TB will require the efforts of all and sundry: the academia, pharmaceutical and biotechnology industries, policymakers, and governmental and nongovernmental organizations (NGO) at local, national, and international levels. The WHO, as the UN agency leading global health initiatives, plays a pivotal role in the worldwide effort to eliminate TB. In 2014 WHO's End-TB Strategy was adopted by the UN World Health Assembly, as part of the Sustainable Development Goals (SDGs). The strategy aims for "ZERO deaths, disease, and suffering due to TB" by implementing a unified global response. It is based on three strategic pillars and supported by four key principles to guide global efforts in combating TB effectively. Encouragingly, United Nations Member States reaffirmed their commitment to the EndTB strategy when they endorsed a political declaration reiterating their commitment to eradicating TB by 2030. WHO regularly publishes reports that provide valuable insights and analyses on emerging trends in AMR and updates on efforts to combat the crisis. One example is the "Global Tuberculosis Report," a comprehensive global report on TB, which gives a global view of the state of the epidemic and the global efforts on the diagnosis, treatment, and prevention of TB. (1) Additionally, TB receives special attention in the WHO's annual report on antimicrobial agents in clinical and preclinical development, which highlights ongoing drug development efforts. In 2017, the WHO published the first Bacterial Priority Pathogens List (BPPL) to prioritize R&D and investments in antimicrobial resistance (AMR). The list categorizes pathogens into critical, high, and medium-priority groups to guide public health interventions. Initially, Mtb was not included, raising concerns in the anti-TB community. However, the 2024 update to the BPPL now includes drug-resistant Mtb as a critical priority organism, marking an important step in drawing attention to the concern of MDR-TB. (37)WHO collaborates with various regional and national governmental and NGOs, such as the U.S. Centers for Disease Control and Prevention (CDC), the European Centre for Disease Prevention and Control (ECDC), the African Centre for Disease Control, and the Indian National Centre for Disease Control, in advancing the End-TB strategy. Additionally, global partners such as the KNCV Tuberculosis Foundation, the International Union Against Tuberculosis and Lung Disease, the Bill and Melinda Gates Foundation, the TB Alliance, the Stop TB Partnership, the United States Agency for International Development (USAID), Tuberculosis Vaccine Initiative (TBVI), the Global Fund, etc. are key partners in eradicating TB.Guided by USAID's Global TB Strategy 2023–2030, USAID has committed $4.7 billion in bilateral assistance across 24 high-burden TB countries since 2020 to help end the disease. (38) Recently, USAID launched the Global Accelerator to End TB Plus, an initiative designed to enhance the development of effective strategies for a more accountable, inclusive, and responsible TB response. TB Alliance, a nonprofit founded over 20 years ago in South Africa, leads in discovering, developing, and delivering faster-acting, affordable tuberculosis treatments. Another notable group, the Working Group on New Drugs (WGND) under the Stop TB Partnership, serves as an expert forum dedicated to advancing the development of effective and affordable therapies for TB.The urgent need for replenishing the antituberculosis pipeline with novel agents remains a significant challenge for the medicinal chemist, and it necessitates risks and untested approaches. While new chemistries and methodologies are continually emerging, attracting funding and engaging major pharmaceutical companies remains critical. Scientific efforts must be supported by strong policies and financial commitments from governments and NGOs. The global fight against TB requires collective action, leaving no researchers, pharmaceutical firm, philanthropies, nation, or patient behind. As the COVID-19 pandemic taught us, borders alone cannot halt global health threats─scientific solutions, backed by appropriate political will and dedicated resources from the global community, are our best hope. The Journal of Medicinal Chemistry would love to see more research focused on TB and encourage those working in this area to submit your work to the Journal.Author InformationClick to copy section linkSection link copied!Corresponding AuthorCraig W. Lindsley, Warren Center for Neuroscience Drug Discovery and Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States, https://orcid.org/0000-0003-0168-1445, Email: [email protected]AuthorTomayo Berida, Warren Center for Neuroscience Drug Discovery and Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States, https://orcid.org/0000-0002-3578-1033NotesViews expressed in this editorial are those of the authors and not necessarily the views of the ACS.ReferencesClick to copy section linkSection link copied! This article references 38 other publications. 1WHO. Global Tuberculosis Report 2024; Geneva, 2024. https://www.who.int/teams/global-tuberculosis-programme/tb-reports (accessed 2024-11-13).Google ScholarThere is no corresponding record for this reference.2Dheda, K.; Mirzayev, F.; Cirillo, D. M.; Udwadia, Z.; Dooley, K. E.; Chang, K.-C.; Omar, S. V.; Reuter, A.; Perumal, T.; Horsburgh, C. R.; Murray, M.; Lange, C. 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