The heterogeneous evolution of multidrug-resistant Mycobacterium tuberculosis

Abstract

Recent surveillance data of multidrug-resistant tuberculosis (MDR-TB) reported the highest rates of resistance ever documented. As further amplification of resistance in MDR strains of Mycobacterium tuberculosis occurs, extensively drug-resistant (XDR) and totally drug-resistant (TDR) TB are beginning to emerge. Although for the most part, the epidemiological factors involved in the spread of MDR-TB are understood, insights into the bacterial drivers of MDR-TB have been gained only recently, largely owing to novel technologies and research in other organisms. Herein, we review recent findings on how bacterial factors, such as persistence, hypermutation, the complex interrelation between drug resistance and fitness, compensatory evolution, and epistasis affect the evolution of multidrug resistance in M. tuberculosis. Improved knowledge of these factors will help better predict the future trajectory of MDR-TB, and contribute to the development of new tools and strategies to combat this growing public health threat.

Figure 1. The heterogeneity of MDR-TB

A. The proportion of new TB cases with MDR-TB (centre; darker shadings indicate an increasing proportion) [7] is heterogeneously distributed and influenced by a multitude of factors including: B. Variably effective control programs (here, represented by the estimated global case detection rates; darker shadings indicate lower case detection rates) [87]; C. The variable presence of co-morbidities (here, represented by the HIV prevalence among incident TB cases; darker shadings indicate a higher prevalence) [1]; D. Different host-related factors (here, represented by the presence of the HLA II allele DQB1*0503, which was the first HLA allele associated with increased TB risk; darker shading indicates a higher abundance) [88]; and E. The global distribution of different phylogenetic lineages of M. tuberculosis (the six main lineages of human TB-associated strains of M. tuberculosis known to date and their geographical distribution are represented by circles of different colour; the colours correspond to the clades indicated in the phylogenetic tree shown in Figure 4). Figure adapted from www.Globalhealthfacts.org and [7, 89, 90].

Figure 2. A selection of extrinsic and intrinsic factors contributing to the emergence of MDR-TB

A non-exhaustive list of extrinsic, non-bacterial, and intrinsic bacterial factors referred to in the text that modulate the evolution of MDR-TB. Question marks indicate factors that might be involved, but for which there is no direct evidence for in M. tuberculosis.

Figure 3. The influence of Darwinian fitness on the emergence of MDR and XDR-TB

In the absence of drugs, the acquisition of resistance mutations is often associated with a fitness-cost. The most prevalent resistance mutations in clinical isolates show low or no fitness cost. However, high fitness costs incurred by other generally less common mutations can be alleviated by compensatory mutations. Higher and lower fitness levels of bacteria are indicated by small blue or red circles, respectively. Yellow and red arrows and ovals indicate low-cost and high-cost resistance mutations, respectively. Blue arrows and ovals indicate compensatory mutations. Black arrows refer to baseline genomic characteristics of a particular strain genetic background. Figure based on data from [, , –65].

Figure 4. Drug resistance-associated genes containing M. tuberculosis lineage-specific mutations

Phylogenetic tree of the six main lineages of M. tuberculosis associated with human TB, based on 21 whole genome sequences [81]. Genes indicated are associated with drug resistance (Table 1) and harbour lineage-defining, non-synonymous substitutions. This creates the potential for epistatic interactions between the genetic background of a given strain and specific drug resistance-conferring mutations.