Mutations in
            <i>rv0678</i>
            Confer Low-Level Resistance to Benzothiazinone DprE1 Inhibitors in Mycobacterium tuberculosis

Poulton, Nicholas C.; Azadian, Zachary A.; DeJesus, Michael A.; Rock, Jeremy M.

doi:10.1128/aac.00904-22

Cited by 16 publications

(19 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In line with earlier findings, mutations in rv0678 produced cross resistance between CFZ and BDQ 17 . Our study also supports these prior findings that mutations in rv0678 provide resistance to PBTZ-169 (i.e., Macozinone) 32,56 . We also identify a broader range of antibiotics to which mutations in rv0678 provide low-level resistance including Q203.…”

Section: Discussionsupporting

confidence: 91%

See 1 more Smart Citation

The evolution of antibiotic resistance is associated with collateral drug phenotypes inMycobacterium tuberculosis

Waller

Cheung

Cook

et al. 2022

Preprint

View full text Add to dashboard Cite

The increasing incidence of drug resistance in Mycobacterium tuberculosis has diminished the efficacy of almost all available antibiotics, complicating efforts to combat the spread of this global health burden. Alongside the development of new drugs, optimised drug combinations are needed to improve treatment success and prevent the further spread of antibiotic resistance. Typically, antibiotic resistance leads to reduced sensitivity, yet in some cases the evolution of drug resistance can lead to enhanced sensitivity to unrelated drugs. This phenomenon of collateral sensitivity is largely unexplored in M. tuberculosis but has the potential to identify alternative therapeutic strategies to combat drug-resistant strains that are unresponsive to current treatments. To investigate the collateral impacts of drug resistance in M. tuberculosis, we generated an isogenic collection of mono-resistant strains in a PC2-approved avirulent background of M. tuberculosis against 23 structurally and functionally diverse antibiotics. Through drug susceptibility profiling, genomics, and evolutionary studies we provide evidence for the existence of collateral drug sensitivity in M. tuberculosis. In proof-of-concept studies, we demonstrate how collateral drug phenotypes can be targeted to select against and prevent the emergence of drug-resistant strains of M. tuberculosis. This study highlights that the evolution of drug resistance in M. tuberculosis leads to collateral drug responses that can be exploited to design improved drug regimens.

show abstract

Section: Discussionsupporting

confidence: 91%

“…Consistent with this, rv0678 mutants were selected for in the presence of PBTZ-169 (Figure 1). These observations validate recent chemical-genetic screens investigating resistance mechanisms to PBTZ-169 32 . Mutations in rv0678 also provided low-level resistance (i.e., 2-3-fold) to Q203 and AZ7371 (AZ7) (Figure 1).…”

Section: And S1a)supporting

confidence: 84%

The evolution of antibiotic resistance is associated with collateral drug phenotypes inMycobacterium tuberculosis

Waller

Cheung

Cook

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…For example, mutations in the transcriptional repressor gene rv0678 lead to crossresistance to bedaquiline and clofazimine due to derepression of mmpL5-mmpS5 efflux pump operon [8]. Even more frightening is a recent report that the same type of mutations may also lead to low-level resistance to promising new drugs in the benzothiazinone group PBTZ169 and BTZ043 [9].…”

Section: Discussionmentioning

confidence: 99%

Perсhlozone Resistance in Clinical Isolates of Mycobacterium tuberculosis

Ushtanit¹,

Mikhaïlova²,

Krylova³

et al. 2023

Preprint

View full text Add to dashboard Cite

The emergence of drug-resistant tuberculosis forced the development of new drugs and screnning of more effective or less toxic analogs. Mycolic acids biosynthesis is targeted by several antituberculosis drugs toped by the isoniazid being one of the most important in tuberculosis therapy. Recently, perchlozone, acting on another step in FAS-II cycle, received official approval and was included in the Russian national clinical guidelines. Using the serial dilution method on agar 7H10 plates for perchlozone and Sensititre MYCOTB microdilution plate we analyzed the phenotypic properties of primary M. tuberculosis clinical isolates and analyzed the molecular determinants of resistance to isoniazid, ethionamide and perchlozone. We found a wide variation in the MIC of perchlozone from 2 to 64 mg/L, correlating with the overall resistance profile: the MIC was higher for MDR and pre-XDR isolates. The cross-resistance between the ethionamide and the perchlozone was driven by mutations in ethA gene encoding monooxygenase responsible for activation of both drugs. Presumably susceptible to perchlozone wild-type strains had MICs ranged 2–4 mg/L, and the breakpoint estimated to be at 4 or 8 mg/L. In conclusion, susceptibility to perchlozone retained for a part of MDR strains, as does suceptibility to ethionamide, providing the possibility of therapy for such cases based on phenotypic or molecular analysis.

show abstract

“…For example, mutations in the transcriptional repressor gene rv0678 lead to cross-resistance to bedaquiline and clofazimine due to derepression of the mmpL5 - mmpS5 efflux pump operon [ 29 ]. Even more frightening is a recent report that the same type of mutations may also lead to low-level resistance to promising new drugs from the benzothiazinone group PBTZ169 and BTZ043 [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Perchlozone Resistance in Clinical Isolates of Mycobacterium tuberculosis

Ushtanit

Mikhailova²,

Krylova³

et al. 2023

Antibiotics

View full text Add to dashboard Cite

The emergence of drug-resistant tuberculosis forced the development of new drugs and the screening of more effective or less toxic analogues. Mycolic acid biosynthesis is targeted by several antituberculosis drugs, isoniazid being one of the most important in tuberculosis therapy. Recently, perchlozone, acting on another step in the FAS-II cycle, was officially approved for tuberculosis treatment in the Russian Federation and was included in the Russian national clinical guidelines. Using the serial dilution method on 7H10 agar plates for perchlozone and a Sensititre MYCOTB microdilution plate, we analyzed the phenotypic properties of primary clinical isolates of M. tuberculosis and analyzed the molecular determinants of resistance to isoniazid, ethionamide, and perchlozone. We found a wide variation in the MIC of perchlozone from 2 to 64 mg/L, correlating with the overall resistance profile: the MIC was higher for MDR and pre-XDR isolates. The cross-resistance between ethionamide and perchlozone was driven by mutations in the ethA gene encoding monooxygenase responsible for the activation of both drugs. The presumably susceptible to perchlozone and wild-type strains had MICs ranging from 2 to 4 mg/L, and the breakpoint was estimated to be 4 or 8 mg/L. In conclusion, susceptibility to perchlozone is retained for a part of the MDR strains, as is susceptibility to ethionamide, providing the possibility of therapy for such cases based on phenotypic or molecular analysis.

show abstract

Mutations in rv0678 Confer Low-Level Resistance to Benzothiazinone DprE1 Inhibitors in Mycobacterium tuberculosis

Abstract: Tuberculosis (TB) is the leading cause of death from any bacterial infection, causing 1.5 million deaths worldwide each year. Due to the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb) there have been significant efforts aimed at developing novel drugs to treat TB.

Cited by 16 publications

References 60 publications

The evolution of antibiotic resistance is associated with collateral drug phenotypes inMycobacterium tuberculosis

The evolution of antibiotic resistance is associated with collateral drug phenotypes inMycobacterium tuberculosis

Perсhlozone Resistance in Clinical Isolates of Mycobacterium tuberculosis

Perchlozone Resistance in Clinical Isolates of Mycobacterium tuberculosis

Contact Info

Product

Resources

About