Antimicrobial resistance in Mycobacterium tuberculosis: mechanistic and evolutionary perspectives
TL;DR: Although the genetic diversity of M. tuberculosis is low compared to other pathogenic bacteria, the strain genetic background has been demonstrated to influence multiple aspects in the evolution of drug resistance.
Abstract: Antibiotic-resistant Mycobacterium tuberculosis strains are threatening progress in containing the global tuberculosis epidemic. Mycobacterium tuberculosis is intrinsically resistant to many antibiotics, limiting the number of compounds available for treatment. This intrinsic resistance is due to a number of mechanisms including a thick, waxy, hydrophobic cell envelope and the presence of drug degrading and modifying enzymes. Resistance to the drugs which are active against M. tuberculosis is, in the absence of horizontally transferred resistance determinants, conferred by chromosomal mutations. These chromosomal mutations may confer drug resistance via modification or overexpression of the drug target, as well as by prevention of prodrug activation. Drug resistance mutations may have pleiotropic effects leading to a reduction in the bacterium's fitness, quantifiable e.g. by a reduction in the in vitro growth rate. Secondary so-called compensatory mutations, not involved in conferring resistance, can ameliorate the fitness cost by interacting epistatically with the resistance mutation. Although the genetic diversity of M. tuberculosis is low compared to other pathogenic bacteria, the strain genetic background has been demonstrated to influence multiple aspects in the evolution of drug resistance. The rate of resistance evolution and the fitness costs of drug resistance mutations may vary as a function of the genetic background.
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TL;DR: Owing to recent advances in whole-genome sequencing and analyses of large collections of MTBC clinical isolates from around the world, many new insights have been gained, including a better understanding of the origin of the MTBC as an obligate pathogen and its molecular evolution and population genetic characteristics both within and between hosts, as well as many aspects related to antibiotic resistance.
Abstract: Tuberculosis (TB) is the number one cause of human death due to an infectious disease. The causative agents of TB are a group of closely related bacteria known as the Mycobacterium tuberculosis complex (MTBC). As the MTBC exhibits a clonal population structure with low DNA sequence diversity, methods (such as multilocus sequence typing) that are applied to more genetically diverse bacteria are uninformative, and much of the ecology and evolution of the MTBC has therefore remained unknown. Owing to recent advances in whole-genome sequencing and analyses of large collections of MTBC clinical isolates from around the world, many new insights have been gained, including a better understanding of the origin of the MTBC as an obligate pathogen and its molecular evolution and population genetic characteristics both within and between hosts, as well as many aspects related to antibiotic resistance. The purpose of this Review is to summarize these recent discoveries and discuss their relevance for developing better tools and strategies to control TB.
349 citations
TL;DR: Focusing on sequence-based discovery of antibiotic resistance genes, this Review discusses computational strategies and resources for resistance gene identification in genomic and metagenomic samples, including recent deep-learning approaches.
Abstract: Antimicrobial resistance extracts high morbidity, mortality and economic costs yearly by rendering bacteria immune to antibiotics. Identifying and understanding antimicrobial resistance are imperative for clinical practice to treat resistant infections and for public health efforts to limit the spread of resistance. Technologies such as next-generation sequencing are expanding our abilities to detect and study antimicrobial resistance. This Review provides a detailed overview of antimicrobial resistance identification and characterization methods, from traditional antimicrobial susceptibility testing to recent deep-learning methods. We focus on sequencing-based resistance discovery and discuss tools and databases used in antimicrobial resistance studies.
278 citations
TL;DR: The art of repurposing existing drugs for antimicrobial purposes is covered, including the potential opportunities for finding new uses as antimicrobials for existing drugs, the approaches used for screening and the scientific, intellectual property and regulatory challenges to be overcome.
Abstract: Antimicrobial resistance continues to be a public threat on a global scale. The ongoing need to develop new antimicrobial drugs that are effective against multi-drug-resistant pathogens has spurred the research community to invest in various drug discovery strategies, one of which is drug repurposing—the process of finding new uses for existing drugs. While still nascent in the antimicrobial field, the approach is gaining traction in both the public and private sector. While the approach has particular promise in fast-tracking compounds into clinical studies, it nevertheless has substantial obstacles to success. This Review covers the art of repurposing existing drugs for antimicrobial purposes. We discuss enabling screening platforms for antimicrobial discovery and present encouraging findings of novel antimicrobial therapeutic strategies. Also covered are general advantages of repurposing over de novo drug development and challenges of the strategy, including scientific, intellectual property and regulatory issues. This Review describes the potential opportunities for finding new uses as antimicrobials for existing drugs, the approaches used for screening and the scientific, intellectual property and regulatory challenges to be overcome.
190 citations
TL;DR: The aim of this review is to provide recent updates on drug resistance mechanisms, newly developed/repurposed anti‐TB agents in pipeline and international recommendations to manage MDR‐TB, based on recent literature and WHO guidelines and aims to facilitate better understanding of drug resistance for effective TB therapy and clinical management.
Abstract: Tuberculosis (TB) along with acquired immune deficiency syndrome and malaria rank among the top three fatal infectious diseases which pose threat to global public health, especially in middle and low income countries. TB caused by Mycobacterium tuberculosis (Mtb) is an airborne infectious disease and one-third of the world's population gets infected with TB leading to nearly 1·6 million deaths annually. TB drugs are administered in different combinations of four first-line drugs (rifampicin, isoniazid, pyrazinamide and ethambutol) which form the core of treatment regimens in the initial treatment phase of 6-9 months. Several reasons account for the failure of TB therapy such as (i) late diagnosis, (ii) lack of timely and proper administration of effective drugs, (iii) lower availability of less toxic, inexpensive and effective drugs, (iv) long treatment duration, (v) nonadherence to drug regimen and (vi) evolution of drug-resistant TB strains. Drug-resistant TB poses a significant challenge to TB therapy and control programs. In the background of worldwide emergence of 558 000 new TB cases with resistance to rifampicin in the year 2017 and of them, 82% becoming multidrug-resistant TB (MDR-TB), it is essential to continuously update the knowledge on the mechanisms and molecular basis for evolution of Mtb drug resistance. This narrative and traditional review summarizes the progress on the anti-tubercular agents, their mode of action and drug resistance mechanisms in Mtb. The aim of this review is to provide recent updates on drug resistance mechanisms, newly developed/repurposed anti-TB agents in pipeline and international recommendations to manage MDR-TB. It is based on recent literature and WHO guidelines and aims to facilitate better understanding of drug resistance for effective TB therapy and clinical management.
149 citations
Cites background or methods from "Antimicrobial resistance in Mycobac..."
...The over expression of Eis might be the first step towards evolution of high resistance towards aminoglycoside/cyclic peptide in the future (Chen et al. 2012; Houghton et al. 2013; Gygli et al. 2017)....
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...Classification of drugs used in susceptible-TB and MDRTB treatment regimen, as per WHO guidelines 2016 (Da Silva 2011; Hoagland et al. 2016; Rendon et al. 2016; Gygli et al. 2017; Nasiruddin et al. 2017; Tiber et. al....
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...Therefore, Mtb displays co-evolution of virulence and antibiotic resistance (Chen et al. 2012; Houghton et al. 2013; Gygli et al. 2017)....
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...Porins are pore forming proteins present on outer layers of cell wall and they facilitate the entry of hydrophilic compounds, nutrients and small molecules for sustaining Mtb viability and replication (Smith et al. 2013; Nasiri et al. 2017; Gygli et al. 2017)....
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...Table 2 New/repurposed drugs in pipeline (under clinical trials) and compounds under in vitro/preclinical study for treatment of TB (Somoskovi et al. 2001; Hameed et al. 2009; Leibert and Rom 2010; Da Silva 2011; Wang et al. 2013; Gualano et al. 2016; Nasiruddin et al. 2017; Gygli et al. 2017; Lambert et al. 2017; Kaufmann et al. 2017; Koch et al. 2018; Hameed et al. 2018; Honeyborne et al. 2019; Xu et al. 2019)...
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TL;DR: DBGWAS as discussed by the authors uses compacted De Bruijn graphs (cDBG) to gather nodes, identified by the association model, into subgraphs defined from their neighbourhood in the initial cDBG.
Abstract: Genome-wide association study (GWAS) methods applied to bacterial genomes have shown promising results for genetic marker discovery or detailed assessment of marker effect. Recently, alignment-free methods based on k-mer composition have proven their ability to explore the accessory genome. However, they lead to redundant descriptions and results which are sometimes hard to interpret. Here we introduce DBGWAS, an extended k-mer-based GWAS method producing interpretable genetic variants associated with distinct phenotypes. Relying on compacted De Bruijn graphs (cDBG), our method gathers cDBG nodes, identified by the association model, into subgraphs defined from their neighbourhood in the initial cDBG. DBGWAS is alignment-free and only requires a set of contigs and phenotypes. In particular, it does not require prior annotation or reference genomes. It produces subgraphs representing phenotype-associated genetic variants such as local polymorphisms and mobile genetic elements (MGE). It offers a graphical framework which helps interpret GWAS results. Importantly it is also computationally efficient-experiments took one hour and a half on average. We validated our method using antibiotic resistance phenotypes for three bacterial species. DBGWAS recovered known resistance determinants such as mutations in core genes in Mycobacterium tuberculosis, and genes acquired by horizontal transfer in Staphylococcus aureus and Pseudomonas aeruginosa-along with their MGE context. It also enabled us to formulate new hypotheses involving genetic variants not yet described in the antibiotic resistance literature. An open-source tool implementing DBGWAS is available at https://gitlab.com/leoisl/dbgwas.
132 citations
Cites background or methods from "Antimicrobial resistance in Mycobac..."
...aeruginosa [7]: we called the SNPs from a list of 32 known resistance genes and promoters [34, 67, 73]....
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...This species is known for its apparent absence of horizontal gene transfer (HGT) and, accordingly, most of the reported resistance determinants are chromosomal mutations [67] in core genes or gene promoters....
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References
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TL;DR: The complete genome sequence of the best-characterized strain of Mycobacterium tuberculosis, H37Rv, has been determined and analysed in order to improve the understanding of the biology of this slow-growing pathogen and to help the conception of new prophylactic and therapeutic interventions.
Abstract: Countless millions of people have died from tuberculosis, a chronic infectious disease caused by the tubercle bacillus. The complete genome sequence of the best-characterized strain of Mycobacterium tuberculosis, H37Rv, has been determined and analysed in order to improve our understanding of the biology of this slow-growing pathogen and to help the conception of new prophylactic and therapeutic interventions. The genome comprises 4,411,529 base pairs, contains around 4,000 genes, and has a very high guanine + cytosine content that is reflected in the biased amino-acid content of the proteins. M. tuberculosis differs radically from other bacteria in that a very large portion of its coding capacity is devoted to the production of enzymes involved in lipogenesis and lipolysis, and to two new families of glycine-rich proteins with a repetitive structure that may represent a source of antigenic variation.
7,779 citations
"Antimicrobial resistance in Mycobac..." refers background in this paper
...A further peculiarity ofM. tuberculosis is the apparent absence of ongoing horizontal gene transfer (Cole et al. 1998; Gagneux and Small 2007; Bolotin and Hershberg 2015)....
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...tuberculosis is the apparent absence of ongoing horizontal gene transfer (Cole et al. 1998; Gagneux and Small 2007; Bolotin and Hershberg 2015)....
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TL;DR: This article reported Luria and Delbruck's breakthrough study in which they established that viruses do not induce mutations in bacteria, but that virus-resisting mutations are spontaneous.
Abstract: This article reported Luria and Delbruck's breakthrough study in which they established that viruses do not induce mutations
in bacteria, but that virus-resisting mutations are spontaneous. Their "fluctuation test" theory demonstrated that
bacteria were ideal subjects for genetic research.
3,460 citations
TL;DR: The findings suggest that the fitness costs of resistance will allow susceptible bacteria to outcompete resistant bacteria if the selective pressure from antibiotics is reduced, and that the rate of reversibility will be slow at the community level.
Abstract: Most antibiotic resistance mechanisms are associated with a fitness cost that is typically observed as a reduced bacterial growth rate. The magnitude of this cost is the main biological parameter that influences the rate of development of resistance, the stability of the resistance and the rate at which the resistance might decrease if antibiotic use were reduced. These findings suggest that the fitness costs of resistance will allow susceptible bacteria to outcompete resistant bacteria if the selective pressure from antibiotics is reduced. Unfortunately, the available data suggest that the rate of reversibility will be slow at the community level. Here, we review the factors that influence the fitness costs of antibiotic resistance, the ways by which bacteria can reduce these costs and the possibility of exploiting them.
1,929 citations
"Antimicrobial resistance in Mycobac..." refers background in this paper
...To date, we knowof three distinctmechanisms involved in the compensation of fitness costs (Andersson and Hughes 2010)....
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TL;DR: Differences in mycolic acid structure may affect the fluidity and permeability of the bilayer, and may explain the different sensitivity levels of various mycobacterial species to lipophilic inhibitors.
Abstract: Mycobacteria, members of which cause tuberculosis and leprosy, produce cell walls of unusually low permeability, which contribute to their resistance to therapeutic agents. Their cell walls contain large amounts of C60-C90 fatty acids, mycolic acids, that are covalently linked to arabinogalactan. Recent studies clarified the unusual structures of arabinogalactan as well as of extractable cell wall lipids, such as trehalose-based lipooligosaccharides, phenolic glycolipids, and glycopeptidolipids. Most of the hydrocarbon chains of these lipids assemble to produce an asymmetric bilayer of exceptional thickness. Structural considerations suggest that the fluidity is exceptionally low in the innermost part of bilayer, gradually increasing toward the outer surface. Differences in mycolic acid structure may affect the fluidity and permeability of the bilayer, and may explain the different sensitivity levels of various mycobacterial species to lipophilic inhibitors. Hydrophilic nutrients and inhibitors, in contra...
1,825 citations
"Antimicrobial resistance in Mycobac..." refers background in this paper
...Furthermore, the cell wall contains ‘extractable’ immunogenic glycolipids (Brennan and Nikaido 1995)....
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...Many studies (reviewed in Jarlier and Nikaido 1994; Brennan and Nikaido 1995; Nguyen and Pieters 2009; Sarathy, Dartois and Lee 2012) performed in different mycobacterial species demonstrated that the composition of the cell envelope and the low numbers of porins...
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...The peculiar characteristics of the mycobacterial cell envelope hinder the diffusion of hydrophobic molecules including members of several antibiotics belonging to the classes of macrolides, rifamycins, tetracyclines and fluoroquinolones (Brennan and Nikaido 1995)....
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...Many studies (reviewed in Jarlier and Nikaido 1994; Brennan and Nikaido 1995; Nguyen and Pieters 2009; Sarathy, Dartois and Lee 2012) performed in different mycobacterial species demonstrated that the composition of the cell envelope and the low numbers of porins (Mailaender et al. 2004) contribute…...
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TL;DR: MDR tuberculosis is more prevalent than previously realised in a rural area in KwaZulu Natal, South Africa and has been transmitted to HIV co-infected patients and is associated with high mortality.
1,601 citations