Abstract
Tuberculosis (TB) is one of the major causes of death related to antimicrobial resistance worldwide because of the spread of Mycobacterium tuberculosis multi- and extensively drug resistant (multi-drug resistant (MDR) and extensively drug-resistant (XDR), respectively) clinical isolates. To fight MDR and XDR tuberculosis, three new antitubercular drugs, bedaquiline (BDQ), delamanid, and pretomanid were approved for use in clinical setting. Unfortunately, BDQ quickly acquired two main mechanisms of resistance, consisting in mutations in either atpE gene, encoding the target, or in Rv0678, coding for the repressor of the MmpS5-MmpL5 efflux pump. To better understand the spreading of BDQ resistance in MDR- and XDR-TB, in vitro studies could be a valuable tool. To this aim, in this work an in vitro generation of M. tuberculosis mutants resistant to BDQ was performed starting from two MDR clinical isolates as parental cultures. The two M. tuberculosis MDR clinical isolates were firstly characterized by whole genome sequencing, finding the main mutations responsible for their MDR phenotype. Furthermore, several M. tuberculosis BDQ resistant mutants were isolated by both MDR strains, harboring mutations in both atpE and Rv0678 genes. These BDQ resistant mutants were further characterized by studying their growth rate that could be related to their spreading in clinical settings. Finally, we also constructed a data sheet including the mutations associated with BDQ resistance that could be useful for the early detection of BDQ-resistance in MDR/XDR patients with the purpose of a better management of antibiotic resistance in clinical settings.
Highlights
According to the World Health Organization (WHO) report, in 2018, tuberculosis (TB), caused by Mycobacterium tuberculosis, was one of the major causes of death related to antimicrobial resistance (World Health Organization [WHO], 2019a)
To better understand the spreading of BDQ resistance in multi-drug resistant (MDR)- and XDR-TB, we reported an in vitro generation of M. tuberculosis mutants resistant to BDQ starting from MDR clinical isolates as parental cultures, since BDQ is used to treat patients affected by MDR-TB
resazurin microtiter assay (REMA) was used to determine the BDQ Minimal Inhibitory Concentration (MIC) values of both isolates (MIC = 0.06 μg/ml, as for the H37Rv wild-type strain). This MIC value (0.06 μg/ml) for M. tuberculosis BDQ sensitive strains is in agreement with that proposed in 7H9 medium by both EUCAST and previously (Kaniga et al, 2016; EUCAST, 2020)
Summary
According to the World Health Organization (WHO) report, in 2018, tuberculosis (TB), caused by Mycobacterium tuberculosis, was one of the major causes of death related to antimicrobial resistance (World Health Organization [WHO], 2019a). In 2018 about half a million TB infections were rifampicin-resistant, of which 78% were multi-drug resistant (MDR)-TB (World Health Organization [WHO], 2019a). Among these cases, 6.2% were estimated to have extensively drug-resistant (XDR)-TB (World Health Organization [WHO], 2019a). 6.2% were estimated to have extensively drug-resistant (XDR)-TB (World Health Organization [WHO], 2019a) Even if it is a relatively small percentage of all MDR-TB cases, these infections are more complicated to treat and to manage and are a challenge for the health systems worldwide. Three new antitubercular drugs, bedaquiline (BDQ) (Janssen, Beerse, Belgium), delamanid (Otsuka, Tokyo, Japan), and pretomanid (TB Alliance) were approved for the treatment of MDR-TB (Li et al, 2019; Nieto Ramirez et al, 2020). Several studies demonstrated that patients treated with a BDQ-containing regimen showed a high culture conversion rate (65–100%) (Li et al, 2019; Pontali et al, 2019)
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