Exploiting evolutionary trade-offs for posttreatment management of drug-resistant populations

Melnikov, Sergey; Stevens, David L.; Fu, Xian; Kwok, Hui Si; Zhang, Jintao; Shen, Yue; Sabina, Jeffery; Lee, Kevin; Lee, Harry; Söll, Dieter

doi:10.1073/pnas.2003132117

Cited by 21 publications

(17 citation statements)

References 65 publications

(85 reference statements)

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“…Specifically, we demonstrated that the combination of EPT with norvaline reduces the emergence of M. abscessus and M. tuberculosis mutants and results in increased activity in vivo compared to EPT. Whether norvaline can be a therapeutic adjunct for other benzoxaboroles remains to be established, but is supported by observations with tavaborole and norvaline in E. coli [45]. The potential for combination therapy may be of value in non-mycobacterial applications, such as the treatment of urinary tract infections, where EPT did not progress beyond phase 2 studies owing to the rapid emergence of resistance [30].…”

Section: Discussionmentioning

confidence: 99%

Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline

et al. 2021

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Mycobacterium abscessus is the most common rapidly growing non-tuberculous mycobacteria to cause pulmonary disease in patients with impaired lung function such as cystic fibrosis. M. abscessus displays high intrinsic resistance to common antibiotics and inducible resistance to macrolides like clarithromycin. As such, M. abscessus is clinically resistant to the entire regimen of front-line M. tuberculosis drugs, and treatment with antibiotics that do inhibit M. abscessus in the lab results in cure rates of 50% or less. Here, we identified epetraborole (EPT) from the MMV pandemic response box as an inhibitor against the essential protein leucyl-tRNA synthetase (LeuRS) in M. abscessus. EPT protected zebrafish from lethal M. abscessus infection and did not induce self-resistance nor against clarithromycin. Contrary to most antimycobacterials, the whole-cell activity of EPT was greater against M. abscessus than M. tuberculosis, but crystallographic and equilibrium binding data showed that EPT binds LeuRSMabs and LeuRSMtb with similar residues and dissociation constants. Since EPT-resistant M. abscessus mutants lost LeuRS editing activity, these mutants became susceptible to misaminoacylation with leucine mimics like the non-proteinogenic amino acid norvaline. Proteomic analysis revealed that when M. abscessus LeuRS mutants were fed norvaline, leucine residues in proteins were replaced by norvaline, inducing the unfolded protein response with temporal changes in expression of GroEL chaperonins and Clp proteases. This supports our in vitro data that supplementation of media with norvaline reduced the emergence of EPT mutants in both M. abscessus and M. tuberculosis. Furthermore, the combination of EPT and norvaline had improved in vivo efficacy compared to EPT in a murine model of M. abscessus infection. Our results emphasize the effectiveness of EPT against the clinically relevant cystic fibrosis pathogen M. abscessus, and these findings also suggest norvaline adjunct therapy with EPT could be beneficial for M. abscessus and other mycobacterial infections like tuberculosis.

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Section: Discussionmentioning

confidence: 99%

Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline

et al. 2021

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“…Whether norvaline can be a therapeutic adjunct for other benzoxaboroles remains to be established, but is supported by observations with tavaborole and norvaline in E. coli . 41 The potential for combination therapy may be of value in non-mycobacterial applications, such as the treatment of urinary tract infections, where EPT did not progress beyond phase 2 studies owing to the rapid emergence of resistance. 15…”

Section: Discussionmentioning

confidence: 99%

Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline

Sullivan

Lupien

Kalthoff

et al. 2021

Preprint

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Certain aminoacyl-tRNA synthetases developed a proofreading mechanism to ensure aminoacylation of tRNAs with cognate amino acids. Epetraborole (EPT) was identified as an inhibitor of the leucyl-tRNA synthetase (LeuRS) editing site in Mycobacterium abscessus. EPT displayed enhanced activity against M. abscessus over Mycobacterium tuberculosis. Crystallographic and equilibrium binding data showed that EPT binds LeuRSMabs and LeuRSMtb with similar Kd. Proteomic analysis revealed that when M. abscessus LeuRS mutants were fed the non-proteinogenic amino acid norvaline, leucine residues in proteins were replaced by norvaline, inducing expression of GroEL chaperonins and Clp proteases. In vitro data revealed that supplementation of media with norvaline reduced the emergence of EPT mutants in both M. abscessus and M. tuberculosis. The combination of EPT and norvaline had improved in vivo efficacy compared to EPT in a murine model of M. abscessus infection.

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“…However, their inclusion is more likely to enhance the impact of adaptive therapy than diminish it due to the potential for increasing the cost of resistance (e.g. [22,61,62]).…”

Section: Discussionmentioning

confidence: 99%

Spatial structure impacts adaptive therapy by shaping intra-tumoral competition

Strobl

Gallaher

West

et al. 2020

Preprint

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(1) Background: Adaptive therapy aims to tackle cancer drug resistance by leveraging intra-tumoural competition between drug-sensitive and resistant cells. Motivated by promising results in prostate cancer there is growing interest in extending this approach to other cancers. Here we present a theoretical study of intra-tumoural competition during adaptive therapy, to identify under which circumstances it will be superior to aggressive treatment, and how it can be improved through combination treatment; (2) Methods: We study a 2-D, on-lattice, agent-based tumour model. We examine the impact of different micro-environmental factors on the comparison between continuous drug administration and the adaptive schedule pioneered in the first-in-human clinical trial. (3) Results: We show that the degree of crowding, the initial resistance fraction, the presence of possible resistance costs, and the rate of tumour cell turnover are key determinants of the benefit of adaptive therapy. Subsequently, we investigate whether combination with treatments which amplify proliferation or which target cell turnover can prolong tumour control. While the former increases competition, we find that only the latter can robustly improve time to progression; (4) Conclusion: Our work helps to identify selection factors for adaptive therapy and provides stepping stones towards the rational design of multi-drug adaptive regimens.

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Exploiting evolutionary trade-offs for posttreatment management of drug-resistant populations

Cited by 21 publications

References 65 publications

Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline

Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline

Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline

Spatial structure impacts adaptive therapy by shaping intra-tumoral competition

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