The Mycobacterium bovis BCG GroEL1 Contributes to Isoniazid Tolerance in a Dormant-Like State Model

Due to the Mycobacterium tuberculosis complex, including M. tuberculosis and M. bovis, tuberculosis still causes 1.6 million deaths per year. Therefore, efforts to improve tuberculosis treatment are necessary. We previously showed that the GroEL1 protein is involved in antibiotic intrinsic resistance. Indeed, the M. bovis BCG cpn60.1 gene (encoding GroEL1)-disrupted strain (Δcpn60.1) exhibits higher rifampicin and vancomycin susceptibility due to defective cell wall integrity. Here, we show that during hypoxia-triggered growth stasis, in the Wayne dormancy model, the mutant exhibited comparable rifampicin and ethionamide susceptibility but higher isoniazid susceptibility compared to the wild-type strain. Although the Δcpn60.1 strain showed compromised induction of the DosR regulon, growth stasis was achieved, but an ATP burst and a higher reactive oxygen species (ROS) production were observed in the isoniazid-treated Δcpn60.1 strain. GroEL1 could contribute to INH tolerance by reducing ROS.