The Epistatic Landscape of Antibiotic Resistance of Different Clades of Mycobacterium tuberculosis

Abstract

Drug resistance (DR) remains a global challenge in tuberculosis (TB) control. In order to develop molecular-based diagnostic methods to replace the traditional culture-based diagnostics, there is a need for a thorough understanding of the processes that govern TB drug resistance. The use of whole-genome sequencing coupled with statistical and computational methods has shown great potential in unraveling the complexity of the evolution of DR-TB. In this study, we took an innovative approach that sought to determine nonrandom associations between polymorphic sites in Mycobacterium tuberculosis (Mtb) genomes. Attributable risk statistics were applied to identify the epistatic determinants of DR in different clades of Mtb and the possible evolutionary pathways of DR development. It was found that different lineages of Mtb exploited different evolutionary trajectories towards multidrug resistance and compensatory evolution to reduce the DR-associated fitness cost. Epistasis of DR acquisition is a new area of research that will aid in the better understanding of evolutionary biological processes and allow predicting upcoming multidrug-resistant pathogens before a new outbreak strikes humanity.

The Evolution and Transmission Dynamics of Multidrug-Resistant Tuberculosis in an Isolated High-Plateau Population of Tibet, China

“…We used the method proposed by Muzondiwa et al ( 8 ) to assess the risk of different orders of paired resistance ( Fig. 5d ).…”

Genome-Wide Study of Drug Resistant Mycobacterium tuberculosis and Its Intra-Host Evolution during Treatment

“…In spite of a highly conserved pattern of SNPs in dop of pathogenic mycobacteria [ 60 ], in serial isolates comparisons we observed non-synonymous variants within codons 7, 18, and 37, different from those which were described as undergoing mutational shifts with high rates [ 60 ]. A recent study showed that SNP within 37 codon of dop gene was epistatically linked to resistance-associated loci katG :315 and embB :296 in Beijing isolates [ 61 ].…”

The evolving biology of Mycobacterium tuberculosis drug resistance

“…Rifampin (RIF) rpoB rpoA, rpoC (Telenti et al, 1993;Ohno et al, 1996;Ramaswamy and Musser, 1998;Comas et al, 2011;Shea et al, 2021) Pyrazinamide (PZA) pncA pnaB2 (epistatic) (Konno et al, 1967;Scorpio and Zhang, 1996;Muzondiwa et al, 2021) Para-aminosalicylic acid (PAS) thyA thyX-hsdS.1 intergenic region associated, but not shown to be compensatory (Rengarajan et al, 2004;Zhang et al, 2013;Coll et al, 2018) Ethambutol (EMB) embCAB operon aftA (Rv3792) (Alcaide et al, 1997;Telenti et al, 1997;Safi et al, 2013) Isoniazid (INH) katG, inhA ahpC promoter (Zhang et al, 1992;Heym et al, 1995;Sherman et al, 1996) Fluoroquinolones (FQ) gyrA Extragenic Rv0890c, Insertions in glgC in Mycobacterium aurum (Takiff et al, 1994;Pi et al, 2020) Bedaquiline (BDQ) mmpR (Rv0678), atpE, pepQ atpB? (suggested) (Andries et al, 2005;de Jonge et al, 2007;Huitric et al, 2010;Andries et al, 2014;Nieto Ramirez et al, 2020) Clofazimine (CFZ) pepQ, mmpR Unknown (Almeida et al, 2016) Pretomanid (PA-824)/ Delaminid (DLM)…”