Temporary persistence of bedaquiline-resistant mycobacterium tuberculosis Isolates under bedaquiline pressure as a model to explore resistance mechanisms

Document Type

Article

Department

Pathology and Laboratory Medicine; Paediatrics and Child Health

Abstract

Background: While variants in rv0678 are associated with bedaquiline (BDQ) resistance in Mycobacteriumtuberculosis (Mtb), robust genetic markers to detect resistance are not identified, underscoring the need to explore alternate mechanisms of resistance. Metabolic rerouting is observed for H37Rv under BDQ pressure resulting in a growth lag phase (24–96 h). We used a similar model to study whether variants conferred any selective advantage to BDQ-resistant isolates under BDQ stress.
Methods: Mtb clinical isolates (n = 47) including 9 BDQ-resistant and 38 BDQ-susceptible isolates were selected using convenience sampling. Mtb clinical isolates were subjected to whole-genome Sequencing followed by variant calling and phylogenetic analysis to identify variants in genes associated with BDQ resistance and those involved in noncanonical pathways of resistance. Growth of BDQ-resistant isolates (n = 9) and H37Rv was studied under BDQ pressure (at minimum inhibitory concentration: 0×, 1×, 2.5×, 5×, 7.5×, 10×) over a 0–144 h period.
Results: Phylogenomic analysis showed isolates (n = 47) belonging to; Lineage 3 (n = 42), Lineage 2 (n = 2), Lineage 4 (n = 1), and Lineage 1 (n = 2). Variants in rv0678 (three frameshift and three missense mutations) were identified in 6 BDQ-resistant strains (n = 9) only. Further, nonsynonymous single-nucleotide polymorphisms were found in genes involved in intermediate metabolism (44%) and cell wall processes (31%) in BDQ-resistant isolates. All study isolates and H37Rv showed a lag in growth of 24–96 h. The growth inhibition pattern of BDQ-resistant isolates was similar to each other and H37Rv.
Conclusion: Variants in genes involved in intermediate metabolism and cell wall processes may indicate epistatic mechanisms supporting BDQ resistance and need further exploration. The 24–96 h lag phase is proposed as a model for exploring alternate pathways in the acquisition of BDQ resistance.

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Publication (Name of Journal)

International Journal of Mycobacteriology

DOI

10.4103/ijmy.ijmy_121_24

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