Ancient and recent differences in the intrinsic susceptibility of Mycobacterium tuberculosis complex to pretomanid

Anna Bateson, Julio Ortiz Canseco, Timothy D McHugh, Adam A Witney, Silke Feuerriegel, Matthias Merker, Thomas A Kohl, Christian Utpatel, Stefan Niemann, Sönke Andres, Katharina Kranzer, Florian P Maurer, Arash Ghodousi, Emanuele Borroni, Daniela Maria Cirillo, Maria Wijkander, Juan C Toro, Ramona Groenheit, Jim Werngren, Diana MachadoMiguel Viveiros, Robin M Warren, Frederick Sirgel, Anzaan Dippenaar, Claudio U Köser, Eugene Sun, Juliano Timm

Research output: Contribution to journalArticlepeer-review

Abstract

Objectives: To develop a robust phenotypic antimicrobial susceptibility testing (AST) method with a correctly set breakpoint for pretomanid (Pa), the most recently approved anti-tuberculosis drug. Methods: The Becton Dickinson Mycobacterial Growth Indicator Tube™ (MGIT) system was used at six laboratories to determine the MICs of a phylogenetically diverse collection of 356 Mycobacterium tuberculosis complex (MTBC) strains to establish the epidemiological cut-off value for pretomanid. MICs were correlated with WGS data to study the genetic basis of differences in the susceptibility to pretomanid. Results: We observed ancient differences in the susceptibility to pretomanid among various members of MTBC. Most notably, lineage 1 of M. tuberculosis, which is estimated to account for 28% of tuberculosis cases globally, was less susceptible than lineages 2, 3, 4 and 7 of M. tuberculosis, resulting in a 99th percentile of 2 mg/L for lineage 1 compared with 0.5 mg/L for the remaining M. tuberculosis lineages. Moreover, we observed that higher MICs (≥8 mg/L), which probably confer resistance, had recently evolved independently in six different M. tuberculosis strains. Unlike the aforementioned ancient differences in susceptibility, these recent differences were likely caused by mutations in the known pretomanid resistance genes. Conclusions: In light of these findings, the provisional critical concentration of 1 mg/L for MGIT set by EMA must be re-evaluated. More broadly, these findings underline the importance of considering the global diversity of MTBC during clinical development of drugs and when defining breakpoints for AST.
Original languageEnglish (US)
Pages (from-to)1685-1693
Number of pages9
JournalThe Journal of antimicrobial chemotherapy
Volume77
Issue number6
DOIs
StatePublished - Mar 9 2022
Externally publishedYes

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology
  • Pharmacology (medical)

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