Revisiting the β-Lactams for Tuberculosis Therapy with a Compound-Compound Synthetic Lethality Approach
| Autor: | E. Lucile White, Frank J. Schoenen, Jeffrey Aubé, Hendra Gunosewoyo, Haidan Guo, Clinton Maddox, Lynn Rasmussen, Shiqi Xiao, Warren S. Weiner, Shichun Lun, Shaaretha Pelly, Chunhong Mao, William R. Bishai |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Methyltransferase
Tuberculosis medicine.drug_class Extensively Drug-Resistant Tuberculosis Antibiotics Antitubercular Agents Microbial Sensitivity Tests Drug resistance Synthetic lethality Pharmacology beta-Lactams Meropenem beta-Lactamases Mycobacterium tuberculosis Mice 03 medical and health sciences Mechanisms of Resistance Tuberculosis Multidrug-Resistant medicine Animals Pharmacology (medical) 030304 developmental biology Mice Inbred BALB C 0303 health sciences biology 030306 microbiology Chemistry Potentiator biology.organism_classification medicine.disease Anti-Bacterial Agents Infectious Diseases Female Synthetic Lethal Mutations beta-Lactamase Inhibitors medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 63 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.01319-19 |
| Popis: | The suboptimal effectiveness of β-lactam antibiotics against Mycobacterium tuberculosis has hindered the utility of this compound class for tuberculosis treatment. However, the results of treatment with a second-line regimen containing meropenem plus a β-lactamase inhibitor were found to be encouraging in a case study of extensively drug-resistant tuberculosis (M. C. Payen, S. De Wit, C. Martin, R. Sergysels, et al., Int J Tuberc Lung Dis 16:558-560, 2012, https://doi.org/10.5588/ijtld.11.0414). We hypothesized that the innate resistance of M. tuberculosis to β-lactams is mediated in part by noncanonical accessory proteins that are not considered the classic targets of β-lactams and that small-molecule inhibitors of those accessory targets might sensitize M. tuberculosis to β-lactams. In this study, we screened an NIH small-molecule library for the ability to sensitize M. tuberculosis to meropenem. We identified six hit compounds, belonging to either the N-arylindole or benzothiophene chemotype. Verification studies confirmed the synthetic lethality phenotype for three of the N-arylindoles and one benzothiophene derivative. The latter was demonstrated to be partially bioavailable via oral administration in mice. Structure-activity relationship studies of both structural classes identified analogs with potent antitubercular activity, alone or in combination with meropenem. Transcriptional profiling revealed that oxidoreductases, MmpL family proteins, and a 27-kDa benzoquinone methyltransferase could be the targets of the N-arylindole potentiator. In conclusion, our compound-compound synthetic lethality screening revealed novel small molecules that were capable of potentiating the action of meropenem, presumably via inhibition of the innate resistance conferred by β-lactam accessory proteins. β-Lactam compound-compound synthetic lethality may be an alternative approach for drug-resistant tuberculosis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|