University of Groningen Total Synthesis of Mycolic Acids and Site

University of Groningen Total synthesis of mycolic acids and site-selective functionalization of aminoglycoside antibiotics Tahiri, Nabil IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2019 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Tahiri, N. (2019). Total synthesis of mycolic acids and site-selective functionalization of aminoglycoside antibiotics. University of Groningen. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 27-09-2021 Chapter 1: Mycolic Acids from Mycobacterium tuberculosis 531024-L-sub01-bw-Tahiri Processed on: 3-5-2019 PDF page: 11 Chapter 1 1.1 Mycobacterium tuberculosis 1.1.1 Basic facts The Mycobacterium genus, covering over 150 recognized species,[1] is mostly known for its members that are pathogenic to humans. Of these environmental bacteria, Mycobacterium tuberculosis (M. tb), which causes tuberculosis (TB), is by far the most lethal member of the family. Other well-known pathogenic members include M. ulcerans, which is responsible for Buruli ulcer and M. leprae, also known as Hansen’s bacillus spirally, which causes leprosy. Although these are the three main causative agents for mycobacterium infections worldwide, the amount of newly reported infections for M. leprea (about 250k yearly)[2] and M. ulcerands (5-6k yearly),[3] are in stark contrast with the number of M. tuberculosis infections. On its own, M. tuberculosis already constituted for 10 million estimated infections in 2017.[4] Two thirds of these infections were from eight countries: India (27%), China (9%), Indonesia (8%), the Philippines (6%), Pakistan (5%), Nigeria (4%), Bangladesh (4%) and South Africa (3%). Although the severity of TB infections varies on a national level, clearly, TB is a major burden on most developing countries (Figure 1). Especially in regions where HIV infection rates are relatively high, such as in African nations, TB infection results in higher mortality rates, due to the patient’s compromised immune response. Figure 1. Estimated TB incidence rate by WHO in 2017. Although the total number of people infected with M. tb is estimated by the WHO at around 1.7 billion (23% of the world population!), in most patients TB manifests itself in the form of a latent infection. Especially in developed countries, a latent infection usually goes unnoticed. These patients do not show the typical symptoms (vide infra) associated with TB (Figure 2a), because the tuberculosis bacilli in their body are not active and are fortunately not able to spread this highly contagious disease (in Dutch: 2 531024-L-sub01-bw-Tahiri Processed on: 3-5-2019 PDF page: 12 Mycolic Acids From Mycobacterium Tuberculosis gesloten tbc). However, since 10% of the patients with latent TB develop the active form, which is very contagious (in Dutch: open tbc), treatment should start as soon as TB has been diagnosed. Typical symptoms (Figure 2a) include persistent coughing (with blood), fevers, night sweats, and weight loss (as a result of reduced appetite). Unfortunately, the treatment is not straightforward, as is reflected by the high mortality rate of 1.6 million in 2017 alone, making it the leading cause of death by a single infectious agent worldwide (more than HIV/AIDS).[4] For patients with latent TB, several factors (Figure 2b) such as a HIV infection, cancers, diabetes, alcohol consumption and smoking can significantly increase the likelihood to develop active TB. The latter has been demonstrated to double the mortality rate by active TB in men in India.[5] A) B) Figure 2. A) typical symptoms of TB active patients. B) risk factors for active TB development. Since the physiology of M. tuberculosis highly depends on oxygen, the mammalian respiratory is often its primary target. However, upon spreading to other organs (extrapulmonary tuberculosis), M. tuberculosis can nestle in the pleura (in tuberculous pleurisy), the central nervous system (in tuberculous meningitis), the lymphatic system (in scrofula of the neck), the genitourinary system (in urogenital tuberculosis), and the bones and joints (in Pott disease of the spine).[6] 1.1.2 Treatment and detection If diagnosed in time, the treatment of latent TB is usually executed with a typical regimen consisting of either isoniazid, or isoniazid combined with rifapentine (first-line drugs) over several months. In the case of active TB, treatment is less straightforward, and usually requires the use of the more toxic drugs pyrazinamide and/or ethambutol (also first-line drugs) in combination with the aforementioned ones.[7] Unfortunately, as for most bacteria, the rise of the antibiotic resistance also resulted in reduced activity of the aforementioned first-line antibiotics against multi- and extensively drug resistant TB over the past decades. As a consequence, harsher treatments are applied for combatting these pathogens, and this involves the consecutive addition of more toxic antibiotics to the treatment stack. In a typical regimen against resistant TB, a combination of at least three additional drugs (second-line drugs), on top of the first-line drugs, are applied. This combination contains at least one member of the fluoroquinones[8] (inhibits DNA 3 531024-L-sub01-bw-Tahiri Processed on: 3-5-2019 PDF page: 13 Chapter 1 gyrase, an enzyme necessary for the separation of replicating DNA), aminoglycosides[9] (target bacterial ribosome, thereby hampering protein synthesis) and oxazolidinones[10] (also targets bacterial ribosome, resulting in disruption of the protein translation process) and are administered over an extended period up to two years. Bedaquiline was approved by the FDA in 2012,[11] as part of the accelerated approval program, and is used nowadays as a last resort antibiotic against MDR-TB and XDR-TB in patients for whom the abovementioned drugs are not effective. Needless to say, a combination of these drugs, which on their own can have horrible side effects such as: vomiting, diarrhea, tendon ruptures, serotonin syndrome, psychosis and hearing problems, can affect the patient’s living standard as such, that in some cases continuation of the treatment is irresponsible. As is the case for the treatment, the detection and confirmation of M. tuberculosis can be just as cumbersome and time consuming. When a pneumonia-like illness persist for more than three weeks, a TB infection should be considered as one of the major suspects. Unfortunately, the only method allowing for TB detection with high certainty, is via culturing of a sputum sample and direct observation by microscopy. Because of M. tuberculosis’ extremely slow growth rate, this process can take from 4 up to 8 weeks. Recently, the microscopic observation drug susceptibility (MODS) assay has been proven to be a faster and more sensitive alternative that current culture based test, and additionally allowing for a better resistance type determination.[12] Part of the shortened diagnosis time, is due to the microscopic observation of TB directly from sputum. Since M. tuberculosis can either show up as G+ as G- with gram staining, the acid fast staining is a more widely applied technique. Although not impeccable, the Mantoux test and chest X-rays have been used in conjunction with other tests. 1.2 The cell envelope Parts of the difficulty in the diagnosis and treatment of TB can be attributed to the unusually complex build-up of the cell envelope of M. tuberculosis. The influx of drugs and the natural host defense mechanisms can be greatly influenced by this heavily fortified cell wall. The envelope can be subdivided in three major segments: the inner membrane (also known as plasma membrane), the inner core and the outer membrane. Due to decades of extensive research a more complete picture (as shown in Figure 3) of this complex multiple layered architecture has been constructed thanks to the evolution of modern experimental techniques. At the basis of the envelope lies the inner membrane, which resembles the typical bacterial membrane, and mainly consists of an abundance of glycerophospholipids which are aggregated into a bilayer. This bilayer is made up of mainly phosphatidylinositol (PI), phosphatidylglycerol, phosphatidylserine (PS), phosphatidylethanolamine (PE), cardiolipin (CL), and mannosylated forms of PI (PIMs).[13] Next to these glycerophospholipids, the inner membrane consists of minor 4 531024-L-sub01-bw-Tahiri Processed on: 3-5-2019 PDF page: 14 Mycolic Acids From Mycobacterium Tuberculosis amounts of glycolipids such as lipomannan (LM) and ManLAM. The latter is non- covalently integrated into the bilayer with its lipid moiety, but its polysaccharide segment penetrates deeply into the inner core, bridging both the peptidoglycan (PG) and arabinogalactan (AG) layers, reaching all the way up to the outer membrane. These complex inner plasma lipids fulfill a critical role in the selective permeability of the cell, ATP regulation, DNA replication and electron transport. The inner membrane also consists of a variety of isoprenoids, which serve as carriers during the biosynthesis of some of the most critical components of the cell envelope.[14] Figure 3. Schematic overview of the cell envelope of M. tuberculosis. Light blue symbols represent arabinose residues, red symbols represent galactose residues, brown symbols represent mannose residues, and black circles represent glucose residues.

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