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Trends in the Discovery of New Drugs for Mycobacterium Tuberculosis

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Trends in the Discovery of New Drugs for Mycobacterium Tuberculosis Trends in the discovery of new drugs for Mycobacterium tuberculosis therapy with a glance at resistance Vahid Lohrasbi, Malihe Talebi, Abed Zahedi Bialvaei, Lanfranco Fattorini, Michel Drancourt, Mohsen Heidary, Davood Darban-Sarokhalil To cite this version: Vahid Lohrasbi, Malihe Talebi, Abed Zahedi Bialvaei, Lanfranco Fattorini, Michel Drancourt, et al.. Trends in the discovery of new drugs for Mycobacterium tuberculosis therapy with a glance at resistance. Tuberculosis, Elsevier, 2018, 109, pp.17-27. 10.1016/j.tube.2017.12.002. hal-01801702 HAL Id: hal-01801702 https://hal.archives-ouvertes.fr/hal-01801702 Submitted on 12 Apr 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Tuberculosis 109 (2018) 17–27 Contents lists available at ScienceDirect Tuberculosis journal homepage: www.elsevier.com/locate/tube Review Trends in the discovery of new drugs for Mycobacterium tuberculosis therapy T with a glance at resistance Vahid Lohrasbia, Malihe Talebia, Abed Zahedi Bialvaeia, Lanfranco Fattorinib, ∗ Michel Drancourtc,d, Mohsen Heidarya, Davood Darban-Sarokhalila, a Department of Microbiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran b Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy c Institut Hospital-Universitaire (IHU) Mediterranée Infection, AP-HM, Marseille, France d Aix-Marseille Université, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), UM63, CNRS 7278, IRD 198, INSERM 1095, Marseille, France ARTICLE INFO ABSTRACT Keywords: Despite the low expensive and effective four-drug treatment regimen (isoniazid, rifampicin, pyrazinamide and Mycobacterium tuberculosis ethambutol) was introduced 40 years ago, TB continues to cause considerable morbidity and mortality world- Drug resistance wide. In 2015, the WHO estimated a total of 10.4 million new tuberculosis (TB) cases worldwide. Currently, the Mechanisms increased number of multidrug-resistant (MDR-TB), extensively-drug resistant (XDR-TB) and in some recent New drugs reports, totally drug-resistant TB (TDR-TB) cases raises concerns about this disease. MDR-TB and XDR-TB have MDR lower cure rates and higher mortality levels due to treatment problems. Novel drugs and regimens for all forms XDR fi fi TDR of TB have emerged in recent years. Moreover, scienti c interest has recently increased in the eld of host- HDTs directed therapies (HDTs) in order to identify new treatments for MDR-TB. In this review, we offer an update on the discovery of new drugs for TB therapy with a glance at molecular mechanisms leading to drug resistance in Mycobacterium tuberculosis. 1. Introduction with drug-resistant TB, particularly multidrug-resistant (MDR; caused by MTB strains resistant to at least RIF and INH) or extensively drug- Tuberculosis (TB) is one of the top 10 causes of death worldwide resistant (XDR; caused by MDR MTB strains with additional resistance [1]. Until the late nineteenth century, it amounted to a death sentence to at least one fluoroquinolone (FQ) and 1 s-line injectable drug) need for patients diagnosed with this disease. The discovery of Myco- long, toxic, and expensive drug treatment with a highly unsatisfactory bacterium tuberculosis (MTB) as the causative agent by Robert Koch in proportion of outcomes [6–8]. There is an urgent need for the devel- 1882 paved the way for better treatments of TB [2]. Streptomycin (SM) opment and more efficient evaluation of new TB drugs and shorter (1943) and para-aminosalicylic acid (PAS) (1946) were among the first treatment regimens. The WHO's 2015 annual TB report states that clinically important drugs to be developed [3]. Both showed activity “without new TB drugs and regimens, it will be very difficult to improve against MTB and were rapidly followed by the use of isoniazid (INH) treatment outcomes in the near future” [4]. In this review, we give an (1952), pyrazinamide (PZA) (1952), ethambutol (EMB) (1961) and ri- update on the discovery of new drugs for TB therapy with a glance at fampicin (RIF) (1966) among others. Therefore these two decades were molecular mechanisms leading to current and new drug resistance in called the golden age of TB antibiotics [3]. The introduction of these MTB. drugs for TB treatment immediately led to a sharp and continuous de- cline of TB incidence throughout the world. However, the disease 2. Current drugs suddenly came back in the 1980s in association with the rising epi- demic of the acquired immune deficiency syndrome (AIDS) and the Current drugs are discussed in this part. Table 1 summarizes the emergence of drug-resistant forms [4]. commonly used TB drugs with their genetic basis and related in- The emergence and diffusion of drug-resistant TB is now recognized formation in resistance. as one of the most dangerous threats to global TB control [5]. Patients ∗ Corresponding author. Department of Microbiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran. E-mail addresses: [email protected], [email protected] (D. Darban-Sarokhalil). https://doi.org/10.1016/j.tube.2017.12.002 Received 17 September 2017; Received in revised form 23 November 2017; Accepted 7 December 2017 1472-9792/ © 2017 Elsevier Ltd. All rights reserved. V. Lohrasbi et al. Table 1 Anti-tuberculosis current drugs, MIC, doses, mechanisms of action, major side effects, and genes involved in resistance mutations. Drug (date of discovery) MIC μg/ml Dose per Resistant gene Gene function Mechanism of action Mechanism of drug Major side effects day resistance First-line oral anti-TB drugs Isoniazid (1952) 0.02–0.2 5 mg/kg katG Catalase-peroxidase Inhibits mycolic acid synthesis Decreased drug Peripheral, neuropathy, hepatitis activation inhA NADH-dependent enoyl-acyl carrier Target amplification or protein modification Pyrazinamide (1952) 16–100 30-40 mg/ pncA Pyrazinamidase Activated by pyrazinoic acid, which is Decreased drug Gastrointestinal (GI) upset, rash, joint pain day bacteriocidal activation Rifampicin (1966) 0.05–1 10 mg/day rpoB RNA polymerase Binds to RNA polymerase inhibiting RNA Target modification GI upset, hepatitis synthesis Ethambutol (1961) 1–5 15-25 mg/ embB (not Arabinosyltransferases Inhibits cell wall synthesis Target modification Optic neuritis, decreased visual acuity kg embA,B,C) Injectable anti-TB drugs (injectable agents or parenteral agents) Streptomycin (1943) 2–8 15-20 mg/ rrs 12S ribosomal protein Binds to ribosomal proteins and inhibits Target modification Nephrotoxicity (usually reversible, occurs in 20–25% kg protein synthesis of cases with capreomycin). Occasional irreversible vestibular damage with kanamycin rpsl 16S rRNA Target modification gidB 7-Methylguanosine methyltransferase Target modification Kanamycin (1957) 2–4 15-20 mg/ rrs 16S rRNA Binds to 30S ribosomal subunit inhibiting Target modification kg protein synthesis eis Aminoglycoside acetyltransferase Inactivating mutation – fi 18 Amikacin (1957) 2 4 15-20 mg/ rrs 16S rRNA Disrupts ribosomal function Target modi cation kg eis Aminoglycoside acetyltransferase Inactivating mutation Capreomycin (1960) 2–4 15-20 mg/ rrs 16S rRNA Similar to aminoglycosides Target modification kg tylA rRNA methyltransferase Fluoroquinolones (FQs) Ciprofloxacin (1963) 0.5–2.5 1000 mg gyrA DNA gyrase A Disrupts the DNA-DNA gyrase complex Target modification GI upset inducing double-strand cleavage of DNA, blocking DNA synthesis Ofloxacin (1963) 0.5–2.5 800 mg gyrB DNA gyrase B Target modification Levofloxacin (1963) 0.5–2.5 1000 mg Moxifloxacin (1963) 0.5–2.5 400 mg Gatifloxacin (1963) 0.5–2.5 400 mg Oral bacteriostatic second-line anti-TB drugs D-cycloserine (1955) 10–40 500- alr Alanine racemase Inhibits cell wall synthesis 1000 mg ddl D-Alanine-D-alanine ligase cycA Bacterial D-serine/L- and D-alanine/ glycine/D-cycloserine proton symporter Ethionamide (1956) 2.5–10 15-20 mg/ ethA Mono-oxygenase Inhibits oxygen-dependent mycolic acid Decreased drug GI upset kg synthesis ctivation Tuberculosis 109(2018)17–27 ethR, Transcriptional regulatory repressor Decreased drug protein (TetR family) ctivation inhA NADH-dependent enoyl-acyl carrier Targets amplification protein and modification Para-aminosalicylic acid, 1–8 150 mg/kg thyA Thymidylate synthase Disrupts folic acid metabolism GI upset PAS (1946) ribD Enzyme in riboflavin biosynthesis V. Lohrasbi et al. Tuberculosis 109 (2018) 17–27 2.1. First-line oral anti-TB drugs and has activity against growing bacteria under acidic pH only [31]. One key characteristic of PZA is its ability to inhibit semidormant bacilli 2.1.1. Isoniazid residing in acidic environments [18]. PZA is a pro-drug that has to be Isoniazid (isonicotinic acid hydrazide) is a first-line pro-drug that converted to its active form, pyrazinoic acid (POA), in order for the requires activation by the catalase/peroxidase enzyme encoded by katG pyrazinamidase/nicotinamidase enzyme encoded by the pncA gene of [9]. The active species (isonicotinic acyl radical or anion) reacts with MTB to become active [32]. Pyrazinamide has multiple effects on MTB, nicotinamide adenine dinucleotide (NAD), forming the INH-NAD ad- including interference with membrane energy production, and inhibi- duct, which then inhibits InhA causing inhibition of cell wall mycolic tion of RpsA (ribosomal protein S1), which is involved in translation, acid synthesis. INH is active only against growing MTB, but not against and PanD, which is involved in pantothenate and co-enzyme A synth- non-growing bacilli (9). On the other hand, INH tolerance in non- esis [29,31,33,34]. growing organisms may be caused by the mycobacterial DNA-binding Mutations in the pncA gene are the main mechanism of PZA re- protein 1 (MDP1), a histone-like protein which down-regulates katG sistance in MTB [32,35].
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