Polyketide synthases mutation in tuberculosis transmission revealed by whole genomic sequence, China, 2011-2019

Abstract

Introduction: Tuberculosis (TB) is an infectious disease caused by a bacterium called Mycobacterium tuberculosis (Mtb). Previous studies have primarily focused on the transmissibility of multidrug-resistant (MDR) or extensively drug-resistant (XDR) Mtb. However, variations in virulence across Mtb lineages may also account for differences in transmissibility. In Mtb, polyketide synthase (PKS) genes encode large multifunctional proteins which have been shown to be major mycobacterial virulence factors. Therefore, this study aimed to identify the role of PKS mutations in TB transmission and assess its risk and characteristics. Methods: Whole genome sequences (WGSs) data from 3,204 Mtb isolates was collected from 2011 to 2019 in China. Whole genome single nucleotide polymorphism (SNP) profiles were used for phylogenetic tree analysis. Putative transmission clusters (≤10 SNPs) were identified. To identify the role of PKS mutations in TB transmission, we compared SNPs in the PKS gene region between "clustered isolates" and "non-clustered isolates" in different lineages. Results: Cluster-associated mutations in ppsA, pks12, and pks13 were identified among different lineage isolates. They were statistically significant among clustered strains, indicating that they may enhance the transmissibility of Mtb. Conclusion: Overall, this study provides new insights into the function of PKS and its localization in M. tuberculosis. The study found that ppsA, pks12, and pks13 may contribute to disease progression and higher transmission of certain strains. We also discussed the prospective use of mutant ppsA, pks12, and pks13 genes as drug targets.

Keywords: Mycobacterium tuberculosis; mutation; phylogenetic analysis; polyketide synthases; transmission.

FIGURE 1

Catalytic and mechanistic versatility of ppsA, pks12, pks13. (A) PpsA initiates biosynthesis of phthiocerol products. It does this by extending its substrate using a malonyl-CoA extender unit; the same has been observed for ppsB and ppsC proteins. The ppsD and ppsE proteins add two (R)-methylmalonyl units to the substrate. (B) The pks13 protein consists of five domains, including two acyl carrier protein domains, a β-ketoacyl-synthase, an acyltransferase, and a C-terminal thioesterase (TE) domain, which together contain all the activities required for the condensation of two long-chain fatty acids. (C) There are two complete sets of modules in pks12, which produce mycoketide using five alternating condensations of methylmalonyl and malonyl units. The iterative process would generate a fully saturated chain with branching at each alternate ketide unit.

FIGURE 2

Sample size and lineages proportion in different regions of the 3,204 isolates, China, 2011–2019.

FIGURE 3

Flowchart 1: a flowchart about the process of identification and exclusion of genomic data. M tuberculosis, Mycobacterium tuberculosis; TB, tuberculosis.

FIGURE 4

Phylogenetic tree for lineage2. Green, red and blue branches indicated L2.1, L2.2.2 and L2.2.1 strains, respectively. The inner blue dots indicated the resistance to known antimicrobial drugs. The outermost red dots showed the strains contained SMs.

FIGURE 5

Phylogenetic tree for lineage4. Green, rose red, purple, dark green, red and blue branches indicated sublineage 4.8, sublineage 4.5, sublineage 4, sublineage 4.3 sublineage 4.2 and sublineage 4.4 strains, respectively. The inner blue dots indicated the resistance to known antimicrobial drugs. The outermost red dots showed the strains contained SMs.